Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](Br)[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:21]1[CH:22]=[CH:23][C:15]2[O:14][C:11]3([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[NH:18][C:17](=[O:19])[C:16]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(Br)ccc1O2
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Yield: 99.6 %

Procedure:
6-Bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester (5.00 g, 12.6 mmol) was dissolved in hot DMF (15 ml) and then TEA (5.26 ml, 37.8 mmol), tris(o-tolyl)phosphine (153 mg, 0.504 mmol), Pd(OAc)2 (56 mg, 0.25 mmol) and methyl acrylate (3.25 g, 37.8 mmol) were added at RT. The mixture was heated at 100° C. for 6 h under N2 with a further addition of tris(o-tolyl)phosphine (153 mg, 0.504 mmol) and Pd(OAc)2 (56 mg, 0.25 mmol) after three hours) and then partitioned between brine and AcOEt. The organic phase was rinsed with water and brine, dried over Na2SO4 and evaporated. The residue was triturated in AcOEt and petroleum ether to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (5.05 g)
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[N:12]3[CH:20]=[CH:21][N:22]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH:23]1([CH:26]=[CH:27][C:28]#[N:29])[CH2:25][CH2:24]1.C(#N)C.C1CCN2C(=NCCC2)CC1>ClCCl>[CH:23]1([CH:26]([N:17]2[CH:16]=[C:15]([C:13]3[N:12]4[CH:20]=[CH:21][N:22]=[C:11]4[CH:10]=[C:9]([C:7]4[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=4)[N:14]=3)[CH:19]=[N:18]2)[CH2:27][C:28]#[N:29])[CH2:25][CH2:24]1
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: N#CC=CC1CC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 50 °C
Yield: 58.8 %

Procedure:
To a flask charged with 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.0600 g, 0.2046 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.1048 g, 1.125 mmol) was added 1 mL of acetonitrile and DBU (0.04588 mL, 0.3068 mmol) at ambient temperature with stirring. The flask was then sealed and heated to 50° C. overnight. The reaction mixture was diluted with dichloromethane and loaded directly onto a silica gel column and eluted with ethyl acetate with 0.5% ammonium hydroxide to afford the title compound (0.047 g, 0.1204 mmol, 58.86% yield). MS (apci) m/z=387.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Reactant: Fc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-fluorobenzyl bromide (0.48 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (Na2SO4), evaporation in vacuo afforded 1.38 g (97%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ 7.4-7.2 (m, 5H), 7.0 (m, 1H), 6.75 (m, 2H), 5.4 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.65-2.45 (m, 3H), 2.3 (dd, J=15 and 9 Hz, 1H), 1.1 (d, J=7 Hz, 3H). MS (ES) m/e 334, 366.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@@:9]1([CH3:30])[C@H:14]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:12]2([CH3:13])[C:11](=[O:29])[CH2:10]1)[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)[CH3:8].[Cl-].[NH4+]>O1CCCC1>[CH3:8][CH2:7][C@:9]1([CH3:30])[C@H:14]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:12]2([CH3:13])[C@@H:11]([OH:29])[CH2:10]1)[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3
Reactant: CC[C@]1(C)CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC[C@@]1(C)C[C@H](O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
Lithium aluminum hydride (58 mg; 0.31 mmol) was added to a solution of the 15β-ethyl-15α-methyl ketone (5) (100 mg; 0.31 mmol ) in dry tetrahydrofuran (2 ml) at 0° C. The solution was stirred at 0° C. for 5 min. Saturated aqueous ammonium chloride was added and the mixture was filtered. Standard work-up of the filtrate gave 15β-ethyl-3-methoxy-15α-methylestra-1,3,5(10)-trien-17β-ol (13) (92 mg; 90%), as an oil, [α]D +70° (c 1.0); υmax 3604 cm-1 (OH); δH 0.88 (3H, t, J 7.2 Hz, 15β-CH2CH3), 0.90 (3H, s, 15α-Me), 1.10 (3H, s, 13β-Me), 1.51 obsc (2H, m, 15α-CH2CH3), 1.73 obsc (2H, m, 16α- and 16β-H), 2.84 (2H, m, 6-H2), 3.74 (1H, dd, J 9.9 and 8.2 Hz, 17α-H), 3.78 (3H, s, 3-OMe), 6.63 (1H, d, J 2.8 Hz, 4-H), 6.71 (1H, dd, J 8.4 and 2.8 Hz, 2-H), and 7.21 (1H, d, J 8.4 Hz, 1-H); δC 8.6 (C-152), 13.9 (C-18), 25.9 (C-151), 28.6 (C-11), 29.0 (C-7), 29.9 (C-6), 30.3 (C-12), 36.8 (C-8), 39.0 (15α-Me), 40.0 (C-15), 45.2 (C-9), 45.5 (C-14), 55.2 (3-OMe), 59.6 (C-13), 79.5 (C-16), 80.0 (C-17), 111.4 (C-2), 113.6 (C-4), 126.2 (C-1), 133.0 (C-10), 137.7 (C-5), and 157.5 (C-3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].C(Cl)Cl.[Si](OS([C:28]([F:31])(F)F)(=O)=O)(C)(C)C>O>[CH2:1]([O:3][C:4](=[O:16])[CH:28]([F:31])[CH:6]([CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH3:2]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C=CCOCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(COCc1ccccc1)C(F)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 119.4 %

Procedure:
In a 10 mL flask with 4-benzyloxy-but-2-enoic acid ethyl ester (0.1 g, 0.45 mmol) inside, dry CH2Cl2 3 mL was added under argon. This was cooled to 0° C., TMSOTf (0.08 mL, 0.45 mmol) was added drop by drop. After stirring for 10 min, ethyl α-fluoro silyl enol ether (0.08 g, 0.45 mmol) was added dropwisely at 0° C. This was left stirring at 0° C. for 1.5 hr, at room temperature for 5 hr and refluxing for 25 hr. After cooling to room temperature, H2O was added and the aqueous phase was extracted with CH2Cl2 three times and the combined organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product which was purified by silica gel flash chromatography (Hexane: EtOAc=6:1, Rf==0.42) to give 87.7 mg (59.3%) of the product. 1H NMR (CDCl3, 400 MHz): δ 1.18-1.32 (m, 6H), 2.32-2.54 (m, 2H), 2.77-2.98 (m, 1H), 3.44-3.57 (m, 2H), 4.07-4.30 (m, 4H), 4.45-4.54 (m, 2H), 4.96-5.09 (dd, J=48, 3.2, 1H, minor isomer), 5.10-5.22 (dd, J=48, 3.2, 1H, major isomer), 7.24-7.36 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 14.23, 30.96-31.02 (d, J=6.0), 32.63, 38.51-38.70 (d, J=19), 60.87, 61.73, 67.94-67.99 (d, J=5.0), 68.60-68.63 (d, J=3.0), 73.29-73.35 (d, J=6.0), 86.96-88.81 (d, J=185), 87.54-89.40 (d, J=186), 127.77, 127.87, 128.54, 137.99-138.04 (d, J=5.0), 168.92-169.42 (t, J=25.8), 171.80-171.85 (d, J=5.0). MS (FAB): expected for C17H23FO5 (M+H)+ 327.36. Found 327.16020. IR (neat) νmax 2983, 2938, 2907, 2872, 1760, 1734, 1455, 1374, 1208, 1183, 1090, 1029, 739, 699.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1nc2cccnc2n1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2nc3cccnc3n2Cc2ccccc2)CC1

Procedure:
Grams 2.5 3-benzyl-2-chloro-3H-imidazo[4,5-b]pyridine and 4 ml N-methylpiperazine are heated at 130°-140° C. for 2 hours, then it is cooled, taken up with a few milliliters of chloroform, and separated by chromatography on silica gel column, first eluting with chloroform and then with chloroform:methyl alcohol (95:5). Therefore it is obtained 1 g 3-benzyl-2-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine, which is dissolved in 5 ml absolute ethyl alcohol and added to a solution of 0.8 g fumaric acid in 15 ml absolute ethyl alcohol. It is kept under stirring overnight, the crystallized solid is separated and washed with absolute ethyl alcohol to obtain 0.8 g 3-benzyl-2-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine fumarate melting at 165°-166° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cccnc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(OCc3cccnc3)cc2=O)sc1C(=O)NCc1ccccc1
Reaction time: 0.08 h
Yield: 14.4 %

Procedure:
To a solution of N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide (0.10 g, 0.29 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.028 g, 0.70 mmol) slowly at 0° C. The reaction mixture was stirred for 5 minutes and then 3-(bromomethyl)pyridine hydrobromide (0.096 g, 0.38 mmol) and tetra-n-butylammonium iodide (0.005 g, 0.014 mmol) were added at 0° C. After stirred at ambient temperature for 16 hours, the reaction mixture was concentrated in vacuo to yield a solid residue. The crude product was purified by column chromatography eluted with ethyl acetate/hexanes (50/50 to 100/0) to afford the title compound as a white solid (0.018 g, 14% yield): mp 214-216° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.81-8.61 (m, 4H), 7.98 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, 1H), 7.33-7.19 (m, 5H), 6.42-6.39 (m, 1H), 6.28 (d, J=2.7 Hz, 1H), 5.25 (s, 2H), 5.39 (d, J=5.7 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.3, 161.9, 161.6, 153.9, 150.3, 149.1, 148.7, 139.9, 137.8, 132.3, 128.8, 127.7, 127.2, 124.7, 123.8, 104.3, 97.7, 68.3, 17.5; MS (ES+) m/z 433.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CCOCC>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: CCOCC
Solvent: O
Product: O=C(CN1CCCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-bromo-1-(3-bromophenyl)ethanone (4.0 g, 14.39 mmol) in anhydrous ether (50 mL) was added dropwise to a solution of pyrrolidine (2.05 g, 28.78 mmol) in anhydrous ether (20 mL) at 0° C. The reaction mixture was then warmed to room temperature. After stirring for 2 h, water (80 mL) was added and the aqueous layer was extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over MgSO4 and concentrated to yield 1-(3-bromophenyl)-2-(1-pyrrolidinyl)ethanone as a light yellow oil (3.6 g, 94%), which was used without purification. MS (ES) m/e 268 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])(=[O:16])C.[Na+].CN(C)C=O>O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][OH:16]
Reactant: CC(=O)[O-]
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc2ccccc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 2-chloromethylquinoline hydrochloride (21.4 g), sodium acetate (32.8 g) and N,N-dimethylformamide (200 ml) was stirred at 60° C. overnight. After cooling, the reaction solution was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4N aqueous sodium hydroxide solution (50 ml), tetrahydrofuran (100 ml) and methanol (100 ml) was stirred at room temperature for 1 hour, and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-quinolylmethanol (14.0 g, yield 88%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 68–69° C.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=O)[N:11]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:10]=2[CH:22]=1)=O.C([SiH](CC)CC)C.B(F)(F)F>ClCCCl.CC#N>[Br:1][C:2]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:3]=1[CH2:4][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][CH2:12][N:11]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[C:10]=2[CH:22]=1
Reactant: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)C(=O)CO2)c1cc(I)ccc1Br
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(N1CCOc2ccc(Cc3cc(I)ccc3Br)cc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a stirred solution of 6-(2-bromo-5-iodo-benzoyl)-4-(2,2,2-trifluoro-acetyl)-4H-benzo[1,4]oxazin-3-one (16.0 g, 29.252 mmol) in 1,2-dichloroethane/MeCN (1:2 mixture, 60 mL) was added triethylsilane (9.9 mL, 62.43 mmol) and borontrifluoride diethyletherate complex (4.9 mL, 38.51 mmol) simultaneously at −10° C. After stirring overnight at room temperature, the reaction was heated at 50° C. for 3 h. The reaction was quenched by the addition of aq. sodium bicarbonate (50 mL). Volatiles were evaporated under reduced pressure, and the resulting residue was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with water and brine, then dried over sodium sulfate and concentrated to a residue which was purified by silica gel column chromatography to furnish 1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (12.1 g). MS (ES) m/z 544.7 (M+18)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C)C=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][NH:34][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:30][CH2:31]2)=[CH:11][CH:10]=1
Reactant: Clc1ncccn1
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(CC3CCN(CCNc4ncccn4)CC3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 5.5 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine, 2.12 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight at 60°-70° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 2.6 parts (40%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-2-pyrimidinamine; mp. 125.1° C. (374).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C=C(C)C=C(C)C=1>[OH:1][CH2:6][CH2:5][O:4][CH2:3][C:2]1[NH:15][C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[N:8]=1
Reactant: O=C1COCCO1
Reactant: Nc1cccnc1N
Solvent: Cc1cc(C)cc(C)c1
Product: OCCOCc1nc2ncccc2[nH]1

Procedure:
1,4-Dioxan-2-one (6.13 g, 60 mmol) and 2,3-diaminopyridine (5.46 g, 50 mmol) in mesitylene (100 ml) were heated at reflux in a Dean-Stark separator for 10 h. After cooling, mesitylene was decanted off and the residue was purified by silica gel chromatography (dichloromethane:methanol 9:1) (yield: 8.47 g, 87% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([CH3:25])[CH2:10][CH2:11][O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[CH3:8][CH:9]([CH3:25])[CH2:10][CH2:11][O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1
Reactant: BrCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCCC(C)C)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC(C)C)nc2n1CC1CCOCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (143 mg) in dry DMF (2.42 mL) was added potassium carbonate (217 mg) and the mixture was stirred at 60° C. for 90 mins. The reaction was cooled and 4-(bromomethyl)tetrahydro-2H-pyran (77 mg) was added. The reaction was stirred at 50° C. overnight and was cooled to room temperature. The mixture was taken up in EtOAc (30 mL) and extracted with water (2×15 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give a viscous yellow oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a clear viscous oil (52 mg).
Reaction SMILES: [C:1](/[CH:4]=[C:5](\[CH3:24])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:23])/[CH2:10][CH2:11][C:12](=[O:22])[CH:13]([CH3:21])[CH2:14][S:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1](/[CH:4]=[C:5](\[CH3:24])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:23])/[CH2:10][CH2:11][C:12](=[O:22])[CH:13]([CH3:21])[CH2:14][S:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:33])(=[O:3])[NH2:2]
Reactant: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CS(=O)CC(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Reaction time: 1 h

Procedure:
A solution of 500 mg (0.0014 mol) of methyl [[(6E,10E)-11-carbamoyl-2,6,10-trimethyl-3-oxo-6,10-undecadienyl]thio]acetate in 30 ml of methylene chloride is treated at 0° with 270 mg of m-chloroperbenzoic acid. The solution is stirred at 0° for 1 hour under argon. The reaction solution is washed with aqueous potassium carbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-methanol 3:1. There is obtained methyl [[(6E,10E)-11-carbamoyl-2,6,10-trimethyl-3-oxo-6,10-undecadienyl]sulfinyl]acetate which exhibits the following absorption bands in the IR spectrum: 3329 cm-1, 3197 cm-1, 1734 cm-1, 1671 cm-1, 1639 cm-1, 1610 cm-1, 1439 cm-1, 1307 cm-1, 1218 cm-1, 1193 cm-1, 1148 cm-1, 1016 cm- 1.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[N:19][N:20]([CH:22]2[CH2:25][O:24][CH2:23]2)[CH:21]=1>O1CCCC1>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH:21]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: Brc1cnn(C2COC2)c1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cnn(C3COC3)c2)cc1

Procedure:
4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.5 g, 7.2 mmol) and 4-bromo-1-(oxetan-3-yl)-pyrazole (1.6 g, 7.2 mmol) dissolved in anhydrous tetrahydrofuran (25 mL) are stirred for 3 hours at ambient temperature in the presence of sodium tert-butylate (3.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (101 mg, 0.145 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is purified by chromatography over silica gel using dichloromethane containing diethylamine and ethyl acetate as eluants to yield the expected product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:5][C:4]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)([C:6](O)=[O:7])[CH2:3]1.C1C=C2[N:21]=[N:22]N(O)C2=CC=1.O.O.NN>C(#N)C>[CH3:1][C:2]1([CH3:14])[CH2:5][C:4]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)([C:6]([NH:21][NH2:22])=[O:7])[CH2:3]1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)CC(C(=O)O)(c2cccs2)C1
Agent: NN
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(C(=O)NN)(c2cccs2)C1

Procedure:
3,3-Dimethyl-1-(2-thienyl)cyclobutanecarboxylic acid was reacted with HOBt monohydrate and WSC monohydrochloride in acetonitrile at room temperature. The above reaction solution was added dropwise to an acetonitrile solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 3,3-dimethyl-1-(2-thienyl)cyclobutanecarbohydrazide.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:14][C@H:15]4[N:27]([CH3:28])[CH2:26][CH2:25][C@:21]56[C:22]=3[C:23]=2[O:24][C@H:20]5[C@@H:19]([OH:29])[CH:18]=[CH:17][C@@H:16]46)C(=O)C2=CC=CC=C12.CN.C(Cl)(Cl)Cl>O>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][C@H:15]3[N:27]([CH3:28])[CH2:26][CH2:25][C@:21]45[C:22]=2[C:23]=1[O:24][C@H:20]4[C@@H:19]([OH:29])[CH:18]=[CH:17][C@@H:16]35
Reactant: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CN
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CC[C@]23c4c5ccc(OCCCN)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
To 14 g (29.6 mmol) of 3-O-phthalimidopropyl morphine (13) was added 188 mL of 2M ethanolic methylamine, and the reaction mixture was allowed to stir for 3.5 h at room temperature under nitrogen. The reaction mixture was poured into 650 mL of chloroform and 425 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 3×90 mL of chloroform. The chloroform layers were combined and extracted with 2×140 mL of 1N HCl. The aqueous extract was basified with 140 mL of 2.5 N NaOH and extracted with 3×300 mL of chloroform. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized from diethyl ether to give 8.9 g (26 mmol, 88%) of 14 as a white solid.