Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2)=[C:15]=[O:16].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[CH3:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:14][C:15]([NH:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:7][CH:8]=1)=[O:16])[CH:26]=[CH:25][CH:24]=2
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCC2)cc1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-pyrrolidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.54 (s, 1H), 8.27 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.67 (d, 1H, J=7.5 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.16 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.53 (d, 2H, J=9 Hz), 4.22 (d, 2H, J=6 Hz), 3.20 (m, 4H), 2.63 (s, 3H), 1.94 (m, 4H); MS (ESI) 361 (M+H)+. Anal. Calcd for C22H24N4O.0.2H2O: C, 72.58; H, 6.76; N, 15.39. Found: C, 72.33; H, 6.64; N, 15.22.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH:15]=[CH:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:22])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:22])[CH3:2]
Reactant: CCCC=CC1CCC2c3ccc(OCC)c(F)c3OC2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC1CCC2c3ccc(OCC)c(F)c3OC2C1

Procedure:
5.1 g (about 10.7 mmol) of (E/Z) isomer mixture of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-pent-1-enyl-1,2,3,4,4a,9b-hexahydrodibenzofuran in 50 ml of THF are hydrogenated in a hydrogen atmosphere with addition of 5.0 g of Pd/C (5% Pd). After completion of the uptake of hydrogen (37 h), the reaction solution is filtered and concentrated to dryness. The residue is filtered adsorptively (SiO2, toluene), and the beige solid obtained is re-crystallised repeatedly from isopropanol at room temperature, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-pentyl-1,2,3,4,4a,9b-hexahydro-dibenzofuran as colourless solid (melting point 118° C.).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([CH2:13][CH2:14][CH2:15][C@H:16]([CH2:18][CH2:19][CH2:20]/[C:21](=[CH:23]/[CH2:24][OH:25])/[CH3:22])[CH3:17])[CH3:12])[CH3:7]>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:4])[O:25][CH2:24]/[CH:23]=[C:21](/[CH2:20][CH2:19][CH2:18][C@@H:16]([CH2:15][CH2:14][CH2:13][C@@H:11]([CH2:10][CH2:9][CH2:8][CH:6]([CH3:5])[CH3:7])[CH3:12])[CH3:17])\[CH3:22]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Yield: 92.3 %

Procedure:
2.0 g of methyl isocyanate was added to a solution of 5.0 g of phytol dissolved in 15 ml of methylene chloride. The resulting mixture was refluxed for 6 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: benzene) to obtain 5.5 g (yield: 99.2%) of oily phytyl N-methylcarbamate.
Reaction SMILES: C(=[N:8][CH:9]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])C1C=CC=CC=1.O.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(OCC)C>[NH2:8][CH:9]([P:18]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:19])[C:10]([O:12][CH2:13][C:14]([Cl:16])([Cl:17])[Cl:15])=[O:11].[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(N)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of trichloroethyl N-benzylidene-α-amino-diethylphosphonoacetate (5.69 g., 13.2 mmole) in ethyl ether (25 ml.) is added to a rapidly stirring solution of p-toluenesulfonic acid monohydrate (2.76 g., 14.5 mmole) in ethyl ether (75 ml.). A white precipitate appears immediately. The mixture is stirred for 10 minutes at room temperature, then cooled in ice. The product is collected by suction filtration, washed with cold ethyl ether, and dried in vacuo to give trichloroethyl α-aminodiethylphosphonoacetate, p-toluenesulfonate (6.03 g.) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]2[CH2:33][NH:34][CH2:35][C:28]=12>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:34]2[CH2:33][C:29]3[C:28](=[N:27][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: c1cnc2c(c1)CNC2
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(N2Cc3cccnc3C2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (50.0 mg, 0.189 mmol) was dissolved in THF (3 mL) and then DIPEA (0.0990 mL, 0.568 mmol) was added, followed by the addition of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.0270 g, 0.227 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and water (5 mL) was added to the resulting residue. The aqueous solution was extracted with EtOAc (2×25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 12 g, 30% EA/petroleum ether) to afford 2-chloro-5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazine (29.0 mg, 44.0%) as a brown solid. LCMS Condition B-79: retention time 1.70 min, [M+1]=348.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.38 (br s, 2H), 4.84 (br s, 2H), 6.80 (d, J=2.8 Hz, 1H), 7.25 (dd, J=7.7 Hz, J=4.9 Hz, 1H), 7.35-7.54 (m, 5H), 7.64 (br s, 1H), 7.90 (d, J=2.7 Hz, 1H), 8.34 (d, J=4.3 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:26])=[N:3]1>CO.[C].[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:12]2[CH:11]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:26])[CH:5]=3)=[O:8])[CH:15]=[CH:14][CH:13]=2)=[N:18][CH:19]=1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2)n(C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)cn3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
To a solution of 1,3-dimethyl-N-{3-[(5-nitropyridin-2-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (2.26 g, 6.40 mmol) in methanol (20 mL) was added palladium carbon (50% water-containing product, 200 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.77 g, 86%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:30]([C:27]3[CH:26]=[CH:25][C:24]([Br:23])=[CH:29][N:28]=3)=[O:31])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (264 mg, 0.865 mmol), 5-bromo-pyridine-2-carboxylic acid (192 mg, 0.951 mmol) and HOBT (172 mg, 1.124 mmol) were dissolved in dichloromethane under N2 at 0° C. DIPEA (112 mg, 0.865 mmol) and EDC (182 mg, 0.951 mmol) were added. The mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature, stirred for 17 h at room temperature, quenched with 1M aqueous KHCO3 solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc) to yield the title compound in the form of a colourless solid. 1H-NMR (400 MHz, DMSO-d6, 81° C.): 10.32 (1H, NH), 9.30 (br, 1H), 8.81 (s, 1H), 8.29 (dd, 1H), 8.08 (d, 1H), 7.81 (m, 2H), 7.33 (m, 1H), 7.19 (d, 1H), 4.40-4.30 (m, 2H), 3.75-3.55 (m, 2H), 1.53 (s, 3H), 1.45 (s, 9H); MS: 489 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N1C=CC=CC=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
17.1 2.5 g (9.763 mmol) of 4-chloro-3-nitrobenzenesulfonyl chloride are dissolved in 100 ml of DCM. 1.574 ml (19.5 mmol) of pyridine and 1.086 ml (9.760 mmol) of N-methylpiperazine are added, and the mixture is stirred at room temperature for 14 h. The reaction mixture is washed 3× with water, the organic phase is dried using sodium sulfate, filtered, and the solvent is removed, giving 1-(4-chloro-3-nitrobenzenesulfonyl)-4-methylpiperazine; EI-MS [M]+ 319.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:30][C:31]1[N:32]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:34][C:35]=1[C:36](Cl)=[O:37]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([C:35]3[S:34][C:33]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[N:32][C:31]=3[CH3:30])=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(-c2ccccc2)sc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.45 g, 4.5 mmol) in CH3CN (25 ml), were added triethyl amine (1.56 mL, 11.22 mmol) and 4-methyl-2-phenyl-1,3-thiazole-5-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL) to afford 4-methyl-2-phenyl-thiazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (1.45 g, 66%): mp, 277-279° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=6.96 min. (99%); 1H NMR (DMSO-d6): δ 2.08-2.10 (m, 1H), 2.55-2.59 (m, 2H), 2.66 (s, 3H), 2.86-2.98 (m, 1H), 4.91 (d, J=5.6 Hz, 2H), 5.18 (dd, J=6, 12 Hz, 1H), 7.53-7.98 (m, 8H), 8.91 (t, J=5.6 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 17.20, 30.92, 38.56, 48.87, 121.98, 125.65, 126.65, 126.25, 127.18, 129.37, 130.95, 131.57, 132.36, 133.15, 134.85, 138.83, 155.65, 161.37, 166.14, 166.93, 167.51, 169.82, 172.75. Anal Calcd for C25H20N4O5S: C, 61.47; H, 4.13; N, 11.47; S: 6.56. Found: C, 61.44; H, 4.04; N, 11.63; S: 6.49.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8](=O)[CH3:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[NH4+:12].Cl>>[CH3:1][C:2]1[N:12]=[C:8]([CH3:9])[C:4]([OH:3])=[C:5]([CH3:7])[N:6]=1
Reactant: [NH4+]
Reactant: CC(=O)c1oc(C)nc1C
Agent: Cl
Agent: [OH-]
Product: Cc1nc(C)c(O)c(C)n1
Reaction time: 3 h
Yield: 60 %

Procedure:
The 2,4-dimethyl-5-acetyloxazole is poured into a Parr Bomb with 20 ml (51 mmol) of concentrated ammonium hydroxide and brought to 180° C. in three hours. Heating is continued for 10 hours, and after cooling the mixture is brought to pH 5 with HCl, extracted into ether, dried over Na2SO4 and stripped in vacuo. The residual solid is crystallized from benzene to give pale yellow crystals (1.3 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[C:27](C2C=C3C(I)=CNC3=NC=2)[CH:26]=[CH:25][C:24]=1[CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]3[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:14])=[O:13])[C:5]3=[N:6][CH:7]=2)[CH:26]=[CH:25][C:24]=1[CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(I)c4c3)cc2F)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 48.26 %

Procedure:
Using similar reaction conditions as described in, step ii of Intermediate 1, tert-butyl 4-(2-fluoro-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (400 mg, 0.767 mmol) was tosylated with p-toluene sulfonylchloride (220 mg, 1.151 mmol) and DMAP (282 mg, 2.303 mmol) in DCM (20 mL) to afford 250 mg (48.26% yield) of the titled compound after purification with (60/120 silica gel) column chromatography using 1% methanol in DCM as eluent. MS: m/z=676.3 (M+1). 1H NMR (CDCl3, 300 MHz): δ 8.619-8.611 (d, 1H), 8.12-8.09 (d, 2H), 7.89 (s, 1H), 7.767-7.760 (d, 1H), 7.31-7.23 (m, 5H), 4.26 (s, 2H), 3.08-3.00 (m, 1H), 2.95-2.75 (m, 2H), 2.38 (s, 3H), 1.86-1.64 (m, 4H), 1.489 (s, 9H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:18][C:19]([CH3:21])=[O:20].Cl>O1CCCC1>[Br:9][C:10]1[C:11]([F:17])=[C:12]([C:19]([OH:20])([CH3:21])[CH3:18])[C:13]([F:16])=[CH:14][CH:15]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6.3 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran (standardized beforehand at 0.86M) are introduced under a stream of argon into 5 ml of tetrahydrofuran in a round-bottomed flask. The mixture is cooled to −78° C. and 0.59 ml of 1-bromo-2,4-difluorobenzene is added dropwise thereto. The mixture is stirred at −78° C. for 30 min and acetone is added via four fractions of 0.5 ml. The reaction medium is run into 20 ml of 1N hydrochloric acid after returning to ambient temperature. The organic phase, extracted with diethyl ether, is subsequently washed twice with 20 ml of water, separated, dried over magnesium sulphate and concentrated under reduced pressure. The oil obtained is purified by chromatography on silica gel, elution being carried out with a heptane/ethyl acetate mixture. 0.50 g of compound is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CS(C)=O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:22][CH:23]=1)#[N:26]
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Temperature: 80 °C
Yield: 79 %

Procedure:
15.1 g of 1-(4-hydroxyphenyl)piperazine, 9.4 g of lithium carbonate and 10.4 g of 4-fluorobenzonitrile in 250 ml of dimethyl sulfoxide were reacted at 80° C. for 4 hours under a nitrogen atmosphere. After fresh addition of 3.0 g of 4-fluorobenzonitrile, the mixture was heated at 80° C. for a further 4 hours and the precipitated product was filtered out with suction after cooling the reaction mixture. To separate the co-precipitated lithium carbonate, the crude product was then stirred with aqueous citric acid. After filtering out with suction and drying in a vacuum oven at 60° C., 18.7 g of 4-[4-(4-cyanophenyl)-1-piperazinyl]phenol were obtained, m.p.=258°-262° C.
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:39].O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:19]1[OH:39])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
This compound was prepared using the procedure for palmitoyl-2′-deoxyguanosine, substituting the appropriate amount of guanosine 2′,3′-acylic dialcohol for 2′-deoxyguanosine monohydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[H-].[Na+].C1(C)C=CC(S([O:21][CH2:22][C@@H:23]([CH2:26][CH3:27])[CH2:24]O)(=O)=O)=CC=1>CN(C)C=O>[CH2:26]([C@H:23]([CH2:24][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:22][OH:21])[CH3:27]
Reactant: COc1ccccc1S
Reactant: CC[C@@H](CO)COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](CO)CSc1ccccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
0.47 ml (0.0038 mol) of 2-methoxythiophenol, in solution in 5 ml of dimethylformamide, is added dropwise to a round-bottomed flask, kept under an inert atmosphere, comprising 0.19 g (0.0047 mol) of sodium hydride in suspension in 10 ml of dimethylformamide cooled to 0° C. The mixture is reheated to ambient temperature and stirred for 1 hour, then 0.99 g (0.0038 mol) of 2-(S)-ethyl-3-hydroxypropyl p-toluene-sulfonate (XIXd-1), in solution in 10 ml of dimethyl-formamide, is added. After stirring at ambient temperature for 2 hours, the dimethylformamide is evaporated under high vacuum and the residue is taken up in dichloromethane. The organic phase is washed with water and with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol=98:2). 0.87 g (0.0038 mol) of the title compound (XXd-1) is recovered in the form of an oil.
Reaction SMILES: Cl.F[C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][O:19][C:20]4[C:29]5[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)=[N:16][N:17]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(C)=[O:41]>O1CCOCC1.C(Cl)Cl.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([O:19][CH2:18][C:15]3[N:13]4[CH:14]=[C:9]([C:7]5[NH:8][C:3](=[O:41])[CH:4]=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]4=[N:17][N:16]=3)=[CH:21][CH:22]=[N:23]2)=[CH:28][CH:27]=1
Reactant: CS(C)=O
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cccc(F)n5)cn34)ccnc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5cccc(=O)[nH]5)cn34)ccnc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a pressure vessel, 3N HCl (1.2 ml, 3.5 mmol) was added to 4-((6-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.071 g, 0.18 mmol) in dioxane (0.60 mL). The reaction mixture was then heated at 100° C. for 3.5 h. Concentrated HCl (0.300 mL, 9.9 mmol) was added and the reaction was heated at 100° C. for 2 h. The reaction mixture was concentrated in vacuo, and then dried on high vacuum. Triethylamine (0.74 ml, 5.3 mmol) was added to the compound, and it was allowed to stir for one hour until the free base crashed out of solution. The compound was dissolved partially in DCM/MeOH, however, fully dissolved after addition of hot DMSO. The compound was purified via flash chromatograph, eluting with 0-10% MeOH/NH4OH in DCM. The compound was sonicated in DCM and filtered to remove the triethylamine-hydrochloride salt, and yielded 6-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-methoxyphenyl)piperazine (30 g) in dichloromethane (500 ml) are added triethylamine (22.9 ml) and ethyl chloroformate (15.8 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give ethyl 4-(2-methoxyphenyl)piperazine-1-carboxylate. (2) To a solution of the above product (5 g) in conc. sulfuric acid (18 ml) is added conc. nitric acid (1.31 ml) at 0° C., and the mixture is stirred at around 10° C. for 2 hours. The reaction solution is poured into cold water, and the pH value thereof is adjusted to pH 3 with 2M aqueous sodium hydroxide solution. The resulting precipitates are collected by filtration to give ethyl 4-(2-methoxy-5-nitrophenyl)piperazine-1-carboxylate. (3) The above product (5 g) is dissolved in a mixture of methanol (50 ml) and tetrahydrofuran (50 ml), and thereto is added 2M aqueous sodium hydroxide solution (50 ml), and the mixture is heated under reflux for 18 hours. The reaction solution is diluted with water and ethyl acetate, and the organic layer is washed with saturated brine, dried over magnesium sulfate. To the organic layer is added a 30% solution of hydrogen chloride in ethanol, and the resulting precipitates are collected by filtration to give the title compound (3.52 g).