Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[C:14]3[C:19](=[N:20][CH:21]=2)[N:18]=CN(C)[C:15]3=[O:23])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-:24].[Na+]>CO>[NH2:18][C:19]1[C:14]([C:15]([OH:23])=[O:24])=[N:13][C:12]([N:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)=[CH:21][N:20]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc3ncn(C)c(=O)c3n2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 6-(4-ethylsulfonylpiperazin-1-yl)-3-methyl-pteridin-4-one (5 g, 14.78 mmol) in methanol (51.00 mL) was treated with sodium hydroxide (45.92 mL of 10% w/v, 114.8 mmol) and the reaction mixture stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue diluted with water and neutralised with formic acid. The resulting precipitate was filtered off and the filtrate acidified to pH4 by the addition of formic acid and extracted with dichloromethane. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to give the product as a bright yellow solid (4.66 g, 52% Yield). 1H NMR (400.0 MHz, CDCl3) d 1.45 (3H, t), 3.05 (2H, q), 3.54 (8H, m), 6.05 (2H, br s), 8.21 (1H, s) ppm; MS (ES+) 316
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH:9]=1)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=2)=[O:30])=[CH:17][C:16]=1[NH:31][C:32]1[C:33]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:34]=2[N:35]=[CH:36][N:37]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(NC(=O)OC(C)(C)C)c3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(N)c3)ncnc2n1

Procedure:
The product of Example 108 (0.028 g, 0.044 mmol) was treated with trifluoroacetic acid as in the procedure for Example 96. The crude product was purified by trituration in dichloromethane to give the title compound as a trifluoroacetic acid salt (0.025 g, 87%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.75 (s, 3 H), 6.24 (d, J=8.09 Hz, 1 H), 6.30 (s, 1 H), 6.39 (d, J=7.72 Hz, 1 H), 7.01 (t, J=7.91 Hz, 1 H), 7.12 (d, J=8.82 Hz, 1 H), 7.25-7.40 (m, 2 H), 7.69-7.78 (m, 1 H, 7.82 (d, J=8.82 Hz, 1 H), 8.03 (dd, J=8.64, 2.39 Hz, 1 H), 8.12 (dd, J=17.46, 2.02 Hz, 2 H), 8.88-9.00 (m, 2 H), 10.41 (s, 1 H), 11.60 (s, 1 H); MS (ESI+) m/z 541/543 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1C=O.[OH:15]O>OS(O)(=O)=O.CO.O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[OH:15]
Reactant: OO
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1ccc(O)c(OC)c1OC

Procedure:
A solution of 2,3,4-trimethoxybenzaldehyde (1.00 g, 5.10 mmol) and 30 wt/v % hydrogen peroxide (0.672 mL, 6.52 mmol) in conc. H2SO4 (0.102 mL) and MeOH (10.19 mL) was stirred overnight at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 50% EtOAc in hexanes over 2088 mL) to afford 2,3,4-trimethoxyphenol, as a colorless oil. Rf=0.93 (50% EtOAc/hexanes). LCMS calc.=185.1; found=185.2 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 6.62 (d, J=9.0 Hz, 1 H); 6.55 (d, J=8.9 Hz, 1 H); 5.49 (s, 1 H); 3.94 (s, 3 H); 3.89 (s, 3 H); 3.80 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:16]>CN(C=O)C>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:8][CH:9]1[CH2:10][CH2:11]1)[CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of tert-butyl(cyclopropylmethyl)carbamate (4 g, 23.4 mmol) in DMF (35 mL) was added to a suspension of NaH (60% suspension in mineral oil) (0.58 g, 25.7 mmol) in DMF (5 mL) at 0-5° C., to it was added Iodomethane (2.5 mL, 40 mmol) and stirring was continued at 25° C. for 16 h. Reaction mixture was quenched with cold water, extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (Biotage, Column: silica gel 12 g pack size, solid load, Mobile Phase: EtOAc in n-Hexane: 0 to 5% as eluent) to afford tert-butyl(cyclopropylmethyl)(methyl)carbamate (Int-37) as pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.0-2.9 (2H, d), 2.85 (3H, s), 1.4 (9H, s), 0.9-0.7 (1H, bs), 0.5-0.3 (2H, m), 0.2-0.05 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[CH2:38][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3([CH2:30][O:29][C:28]4[CH:31]=[C:32]5[C:36](=[CH:37][C:27]3=4)[CH2:35][CH2:34][O:33]5)[C:18]2=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1cccc(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using m-toluidine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (81%) as a colorless solid: mp 229-231° C.; 1H NMR (300 MHz, CDCl3) δ8.85 (s, 1H), 7.64-7.55 (m, 2H), 7.49-7.42 (m, 1H), 7.40-7.33 (m, 2H), 7.32-7.16 (m, 4H), 7.11-7.03 (m, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.40 (s, 2H), 5.22-5.05 (m, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.35 (s, 3H); MS (ES+) m/z 525.11 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:22]([O:25][C:26]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)=[CH:45][C:27]=1[C:28]([NH:30][C:31]1[CH:43]=[C:42](Br)[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])(=[O:24])[CH3:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.COCCOC.O>[C:22]([O:25][C:26]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]2)=[CH:45][C:27]=1[C:28]([NH:30][C:31]1[CH:43]=[C:42]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC(=O)Oc1ccc(N2CCCCC2)cc1C(=O)Nc1cc(Br)ccc1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(N2CCCCC2)cc1C(=O)Nc1cc(-c2cccn2C(=O)OC(C)(C)C)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Water (0.60 mL), 1-(tert-butoxycarbonyl)-1H-pyrrole-2-boronic acid (0.024 g), sodium carbonate (0.041 g), and bis(triphenylphosphine)palladium(II) dichloride (2.2 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 2-(2-acetoxy-5-(piperidin-1-yl)benzamido)-4-bromobenzoate (0.080 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and sodium carbonate (0.016 g) was added thereto, followed by heating to reflux under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane/ethyl acetate] to obtain tert-butyl 2-(2-acetoxy-5-(piperidin-1-yl)benzamido)-4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)benzoate.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+:25]>>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:8]2[O:9][C:5]([C:3]([O-:4])=[O:2])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22].[Na+:25]
Reactant: COC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)o1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)[O-])o2)CC1
Yield: 89.7 %

Procedure:
Tert-butyl 4-((5-(methoxycarbonyl)furan-2-yl)methyl)piperazine-1-carboxylate (4.99 g, 15.39 mmol) and sodium hydroxide (0.616 g, 15.39 mmol) were combined and stirred at reflux for 3 hours. The reaction was concentrated under reduced pressure to give the title compound (4.59 g). MS (ESI) m/z 311.4 [M+H]+
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:28]2[CH:27]=[CH:26][C:24]3[N:25]=[C:21]([CH3:20])[S:22][C:23]=3[CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc2ccc(C=O)cc2s1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2nc(C)sc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-methylbenzo[d]thiazole-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 397.01 g/mol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1(C(C)C=O)C=CC=C[CH:26]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.[Pd]>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][CH2:2][CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[CH:26][CH:25]=3)[CH2:9]2)=[O:24])=[CH:22][CH:21]=1
Reactant: O=C(NCC1CN(Cc2ccccc2)CCO1)c1ccc(O)cc1
Reactant: CC(C=O)c1ccccc1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC1CN(CCCc2ccccc2)CCO1)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of N-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide (EXAMPLE 202, Step 1) (55 mg) was dissolved in acetic acid (3 mL) and hydrogenated at 1 atm over 10% Pd/C (50 mg) for 18 h. The catalyst was removed by filtration, washed with acetic acid and the filtrate evaporated, to give an oil. A portion of this oil (21 mg) was dissolved in methanol (1 mL) and treated with phenylpropionaldehyde (24 mg) and sodium cyanoborohydride (25 mg). The resulting reaction was stirred for 15 min and the crude reaction mixture purified by preparative reverse phase IPLC to give the 4-Hydroxy-N-[4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamide compound.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C([O:13][CH2:14][CH2:15][CH:16]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)=[O:24])=O.[OH-].[Na+]>O1CCOCC1>[Cl:42][C:37]1[CH:36]=[C:35]([CH:16]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[C:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[O:24])[CH2:15][CH2:14][OH:13])[CH:40]=[CH:39][C:38]=1[Cl:41]
Reactant: O=C(OCCC(Cn1ccnc1C(=O)c1ccc2ccccc2c1)c1ccc(Cl)c(Cl)c1)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(c1ccc2ccccc2c1)c1nccn1CC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
3-(3,4-Dichlorophenyl)-4-[2-(2-naphthoyl)imidazol-1-yl]butyl 2-naphthoate (1.25 g) (see Preparation 42) was dissolved in 1,4-dioxane (15 ml), 1N aqueous sodium hydroxide solution (4 ml) added and the mixture stirred at room temperature overnight. The dioxane was then removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed sequentially with 1N aqueous sodium hydroxide solution, water and brine and the solvent removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 99:1 changing to 95:5, by volume, dichloromethane:methanol, to give 3-(3,4-dichlorophenyl)-4-[2-(2-naphthoyl)imidazol-1-yl]butan-1-ol (0.8 g) as a gum.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][C:9]([CH2:17][NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:18][CH2:17][C:9]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:10][N:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])[CH2:8]1)=[O:32]
Reactant: CCCS(=O)(=O)N1CC(CN)(c2ccccn2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]methanamine (II-2, 10 mg, 0.04 mmol) in CH2Cl2 (1 mL) was treated with i-Pr2NEt (0.1 mL, 0.58 mmol), 2,4-dichlorobenzoyl chloride (20 μL, 0.14 mmol), and stirred at room temperature. After 3 h, volatiles were removed under a stream of N2 and the residue purified by reverse phase HPLC to afford 2,4-dichloro-N-{[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]methyl}benzamide (II-3) as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH2:3][CH2:4][CH3:5].[CH3:7][C:8]([CH3:13])([CH2:11]O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH2:3][CH2:4][CH3:5])[O:10][CH2:9][C:8]([CH3:13])([CH3:11])[CH2:7][O:6]1
Reactant: CCCC(C)=O
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1(C)OCC(C)(C)CO1

Procedure:
2-Pentanone, 2,2-dimethyl-propane-1,3-diol, and a catalytic amount of p-toluenesulfonic acid (PTSA) were refluxed in toluene to provide a crude product. Distillation provided the product 2,5,5-trimethyl-2-propyl-[1,3]dioxane.
Reaction SMILES: P([O-])(O)(O)=O.[K+].P(=O)(O)(O)O.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)O.[OH-:25].[Na+].[Cl-].[Na+]>O>[CH:19]1([C:17]2[C:16](=[O:12])[CH2:15][CH:14]([OH:25])[CH:13]=2)[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1
Reactant: OC(c1ccco1)C1C=CCCC1
Reactant: [OH-]
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: O
Product: O=C1CC(O)C=C1C1C=CCCC1
Temperature: 100 °C

Procedure:
A mixture of water (800 ml) and potassium dihydrogenphosphate (0.3 g) was heated to 100° C. and then adjusted to pH 5.0 with addition of phosphoric acid. 2-Furyl-2-cyclohexenylcarbinol (20 g) was then added, and the mixture was stirred under reflux for 20 hours while keeping the pH at 5.0. After addition of MgCl2.6H2O (20 g), the mixture was adjusted to pH 7.3 with an aqueous 1N NaOH solution and stirred for 8 hours under reflux. The reaction mixture was cooled, admixed with sodium chloride (20 g) and extracted with methyl isobutyl ketone. The extract was concentrated, and the residue was distilled to give 2-(2-cyclohexenyl)-4-hydroxy-2-cyclopentenone with the yield of 14.2 g (71%). B.P., 140°-145° C./1.5 mmHg.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7].Cl[CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1>CN(C=O)C>[F:13][C:8]1[C:5]([CH:6]=[O:7])=[C:4]([OH:3])[CH:11]=[C:10]([O:12][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH:9]=1
Reactant: ClCc1ccsc1
Reactant: O=Cc1c(O)cc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(O)cc(OCc2ccsc2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
Sodium hydride (0.52 g, 60% dispersion in mineral oil) is added portionwise over 30 minutes to a solution of 2,4-dihydroxy-6-fluorobenzaldehyde (2 g) in DMF (50 mL) at 0° C. The mixture is stirred at 0° C. for 30 minutes then a solution of 3-chloromethylthiophene (1.72 g) in DMF (50 mL) is added and the mixtured stirred at 60° C. for 16 hours. The reaction is concentrated in vacuo and the residue partitioned between diethyl ether (50 mL) and water (50 mL). The aqueous phase is extracted four times with diethyl ether (50 mL) and the combined organic phases washed with brine (50 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:4 v/v). Fractions homogeneous in the required product are combined and evaporated to give a pale yellow solid which is triturated with diisopropyl ether to give 6-fluoro-2-hydroxy-4-(3-thienylmethoxy)benzaldehyde (1.1 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH:23]1([NH:26][C:27](=[O:39])[CH:28]([OH:38])[CH:29]([NH3+:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25][CH2:24]1.ClCCl>CCCCC>[CH:23]1([NH:26][C:27](=[O:39])[CH:28]([OH:38])[CH:29]([NH:37][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[N:5]2[CH:6]=[C:2]([F:1])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4]2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:24][CH2:25]1
Reactant: O=C(O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Reactant: [NH3+]C(Cc1ccccc1)C(O)C(=O)NC1CC1
Agent: [Cl-]
Solvent: CCCCC
Solvent: ClCCl
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1cc(F)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-a minium chloride. The obtained crude product was treated with a mixture of dichloromethane and n-pentane gave 148 mg of the desired product; ESI-MS [M+H]+: 500.2.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: Cc1ccc(B(O)O)cn1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(C)nc2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-methyl-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=62%).
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:54])[C:10]2[N:11]=[CH:12][N:13]([C:52]=2[N:53]=1)[C@@H:14]1[O:51][C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[C@@H:16]([O:17][C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:54])[C:10]2[N:11]=[CH:12][N:13]([C:52]=2[N:53]=1)[C@@H:14]1[O:51][C@H:41]([CH2:42][OH:43])[C@@H:16]([O:17][C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)O[C@@H]2CO[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
N2-isobutyryl-5′-O-(tert-butyldimethylsilyl)-3′-O-(4,4′-dimethoxytrityl)-2′-deoxyguanosine (25 g) was dissolved in 200 ml of dry THF. A THF solution (40 ml) of tetrabutylammonium fluoride was added to the resultant solution and 100 ml of dry THF was further added, followed by stirring at room temperature. After 8 hours, extraction using chloroform was carried out, and the extract was washed by a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. The extract was then concentrated and purified by column chromatography (ethyl acetate/hexane/methanol) to obtain 12.9 g of the titled compound as a white powder (yield: 60%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH3:21][NH2:22]>CN(C)C=O.C(O)C>[CH3:21][NH:22][CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4]
Reactant: CN
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: CNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 150 mg of 2-chloro-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-acetamide (XV) (0.52 mmol) in N,N-dimethylformamide (1.4 mL), 9 mL of a 33% solution of methylamine in ethanol were added (mM). The reaction mixture was stirred at room temperature for 3 hours. The ethanol was then evaporated under reduced pressure and the mixture was diluted with diethyl ether and filtered. A light-yellow solid was then collected, washed with ether then with cold water and dried. The title compound was obtained in moderate yield (100 mg, 68%).