Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@@H:16]([C:22]([N:24]([CH:42]1[CH2:44][CH2:43]1)[CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[N:37]1[CH:41]=[N:40][N:39]=[N:38]1)=[O:27])=[O:23])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O)(C)(C)C>C(Cl)Cl>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][C@H:16]([C:22]([N:24]([CH:42]1[CH2:44][CH2:43]1)[CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[N:37]1[CH:41]=[N:40][N:39]=[N:38]1)=[O:27])=[O:23])[NH2:15]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)NCc1cc(Cl)ccc1-n1cnnn1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H](N)C(=O)N(CC(=O)NCc1cc(Cl)ccc1-n1cnnn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (3 mL) was added to a solution of N-(tert-butoxycarbonyl)-4-methyl-D-leucyl-N1-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-N2-cyclopropylglycinamide (80 mg, 0.15 mmol) in CH2Cl2 (6 mL). The solution was stirred at room temperature for 30 min and the solvent was then removed in vacuo. The residue was taken up in DMF and purified by reverse phase HPLC. The product fractions were combined and reduced in vacuo and the residual oil was concentrated repeatedly from Et2O to give the title compound as a white foam. 1H NMR (500 MHz, CD3O): δ 9.52 (s, 1 H), 8.50 (m, 1 H), 7.68 (d, J=2.5 Hz, 1 H), 7.57 (dd, J=2.5, 8.5 Hz, 1 H), 7.50 (d, J=8.0 Hz, 1 H), 4.72 (dd, J=3.5, 8.5 Hz, 1 H), 4.28 (d, J=16.0 Hz, 1 H), 4.24 (d, J=15.5 Hz, 1 H), 4.10 (d, J=16.0 Hz, 1 H), 3.99 (d, J=16.0 Hz, 1 H), 2.91–2.86 (m, 1 H), 2.02 (dd, J=3.5, 15.5 Hz, 1 H), 1.70 (dd, J=8.5, 15.0 Hz, 1 H), 1.06 (s, 9 H), 1.03–0.86 (m, 4 H). HRMS (APCI, M+H): 434.2055 (found); 434.2066 (calculated).
Reaction SMILES: [CH2:1]=[C:2]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4]>O1CCOCC1.[Pd]>[CH3:1][CH:2]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: C=C(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Yield: 99.2 %

Procedure:
A solution of α-methylenefluorene-2-acetic acid (2.6g.) in dioxane (50ml.) is hydrogenated in the presence of 5% palladium on charcoal (800mg.). The mixture is filtered and the filtrate evaporated to dryness. The residue is sublimed to afford the title compound (2.6g.). The analytical sample is prepared by recrystallization from aqueous methanol, mp 180°-182°.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:6][C:7]1[C:8]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([OH:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: C1=CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)c(C2CCCC2)c(O)c1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
102 g of cyclopentene are added dropwise to 244 g of 3,5-dimethylphenol and 20 g of p-toluene sulphonic acid at 120° C. The mixture is then stirred at this temperature for 2 h. After removal of the catalyst by washing with sodium hydrogen carbonate solution the mixture is fractionated. At boiling point 104° C (0.5 mm Hg) 90 g of 3,5-dimethyl-2-cyclopentylphenol are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)=O>C1(C)C=CC=CC=1.C(O)(=O)C.[Fe]>[NH:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=[C:4]1[C:3]1[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(-c2nc3ccccc3[nH]2)c1
Temperature: 125 °C
Yield: 49.7 %

Procedure:
Iron powder (15.42 g, 280 mmol) was added to a solution of amide 1 (15.00 g, 46.7 mmol) in toluene (125 ml) and acetic acid (60 nil). The mixture was heated at 125° C. for about 1 h (completion of the reaction was monitored by LCMS) and the resulting crude mixture was filtered through a cotton wool plug (to remove iron particles). The crude solution was evaporated to dryness, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried over MgSO4, filtered, and concentrated at reduced pressure. The resulting brown solid was redissolved in CH2Cl2 and few drops of hexane were added to form a solid which was isolated by filtration to give 2 (5.66 g, 42%) as a beige solid: 1H NMR (CD3OD) δ 7.64 (broad s, 2H), 7.30-7.26 (m, 3H), 7.13 (app d, 1H), 6.84 (dd, 1H); MS (ES, positive mode): 244 [M++1].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)([CH3:3])[CH3:2].[OH:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=1>>[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([O:20][C:21]2[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29](=[O:31])[CH3:30])=[CH:25][CH:26]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)/C=C/c1ccc(O)cc1
Product: CC(=O)/C=C/c1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
2-Isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (3.24 g, 12.33 mmol) and (E)-4-(4-hydroxyphenyl)but-3-en-2-one (2.0 g, 12.33 mmol) were reacted in analogy to example 50a. Yield: 304 mg (8%), M+H+: 298.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2].[C:18]([O-])(=[O:20])C.[Na+].C(O)(=O)C.C=O.C([O-])(O)=O.[Na+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH2:18][OH:20])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(C2CCc3nccn32)cc1F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C2CCc3ncc(CO)n32)cc1F

Procedure:
A solution of product from Step H (3.79 g, 16.7 mmol), sodium acetate (2.44 g, 29.7 mmol), acetic acid (1.82 mL, 31.9 mmol), and formaldehyde (37% in water, 15.1 mL) was heated to reflux for 96 hours. The reaction was slowly neutralized by the addition of sat. aq. NaHCO3. The aqueous layer was extracted with methylene chloride (5×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (1→10% MeOH/CHCl3) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]1)[CH:5]=O.[C:22]([C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]2[NH:32][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)=[N:33][C:28]=2[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CN1CCCN(CCCOc2ccc(C=O)cc2Cl)CC1
Product: CN1CCCN(CCCOc2ccc(-c3nc4cc(C(C)(C)C)ccc4[nH]3)cc2Cl)CC1
Yield: 34.1 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (62 mg, 0.20 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (33 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (50 mg, 0.26 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 31 mg (34%) of the title compound. MS (electrospray): mass calculated for C26H35ClN4O, 454.25; m/z found, 455.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.12 (d, J=2.2 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.6 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 4.19 (t, J=6.0 Hz, 2H), 2.84-2.74 (m, 10H), 2.40 (s, 3H), 2.08-1.97 (m, 2H), 1.90-1.83 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[Mg].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1>BrCCBr>[Cl:12][C:13]1[N:14]=[C:15]([Cl:20])[CH:16]=[C:17]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:10])[N:18]=1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [Mg]
Solvent: BrCCBr
Product: Clc1cc(Cc2c(Cl)cccc2Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 2,6-dichlorobenzylchloride (0.102 mol) in 1,1-diethylether (10 ml) was added dropwise to magnesium (0.102 mol) in 1,1-diethylether (60 ml). The reaction was initiated by adding 2 drops of 1,2-dibromoethane. After most of magnesium disappeared, 2,4,6-trichloropyrimidine (0.051 mol) in 1,1-diethylether (30 ml) was added. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/hexane 1/2). The desired fractions were collected and the solvent was evaporated, yielding 3.3 g of (21%) 2,4-dichloro-6-[(2,6-dichloro-phenyl)methyl]pyrimidine (interm. 1; melting point (mp.): 106–107° C.). b) Intermediate (1) (0.0081 mol) in 2-propanol (100 ml) was heated until complete dissolution. The solution was then transferred into a pressure tube and NH3 gas was bubbled into it for 20 minutes. Then the mixture was heated to 80° C. for 16 hours. The solvent was evaporated, yielding a residue of two compounds: 2-chloro-6-[(2,6-di-chloro-phenyl)methyl]-4-pyrimidinamine (interm. 2) and 4-chloro-6-[(2,6-dichloro-phenyl)methyl]-2-pyrimidinamine (interm. 3).
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.[C:22]1(C)C=CC=C[CH:23]=1>>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)[CH3:23]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Product: CCOC(=O)c1cn(CC)c2cc3c(cc2c1=O)OCO3

Procedure:
A melt of 5 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-carboxylate was heated at 220°C for 7 hours and then cooled. The product was thinned with toluene, filtered and recrystallized from chloroform petroleum ether to provide 3.7 g of ethyl 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylate as needles, m.p. 177°-178°C.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][C:31]([O:33]C)=[O:32])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][C:31]([OH:33])=[O:32])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)O5)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of methyl 2-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptan-1-yl)acetate (110 mg, 0.24 mmol) in THF (4 mL) and Methanol (1 mL) was added 1N NaOH (0.72 mL, 0.72 mmol) and the reaction was let stir at rt for 2 hr. The resulting yellow reaction mixture was partially concentrated by rotary evaporation in vacuo (rt water bath). The yellow solution was diluted with MeOH, filtered and purified on preparative HPLC (10-50% MeCN:5 mM NH4OH) to afford 52 mg (49%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 1.63-1.82 (m, 4H), 1.90-2.02 (m, 2H), 2.08-2.21 (m, 2H), 2.79 (s, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.56-7.70 (m, 6H), 10.51 (br. s., 1H). ESI-MS m/z: 448.1 [M+H]+, retention time 1.08 min (condition E). HR/MS [M+H]+: found 448.2236. calc. 448.2218. RT: 2.27 (Condition L).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18]1([S-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+]>CS(C)=O>[C:18]1([S:24][CH2:2][CH2:3][N:4]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([NH2:17])[C:7]=3[N:6]=[CH:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc2ccccc2c2c1ncn2CCCl
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc2ccccc2c2c1ncn2CCSc1ccccc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 8.11 mmol), sodium benzenethiolate (1.79 g, 12.16 mmol), and anhydrous dimethyl sulfoxide (40 mL) under a nitrogen atmosphere. The reaction mixture was heated to 100° C. to give a homogeneous solution that was maintained at 100° C. for 30 minutes at which time the starting material was completely consumed. The hot solution was poured into rapidly stirred water (300 mL) which caused a solid to precipitate out of solution. The solid was collected by filtration to afford an off-white solid. The material was triturated with acetonitrile and collected by filtration to give 1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.08 g, 6.49 mmol) as an off-white powder, m. p. 233-235° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][CH2:39][CH2:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:47]2[CH:48]=[CH:49][C:44]([S:41]([CH2:40][CH2:39][O:38][CH3:37])(=[O:42])=[O:43])=[CH:45][CH:46]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 59 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 2.14 g, 4 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (prepared as in Example 88, 2.5 g, 10 mmol) and dichlorobis(triphenylphosphine)palladium (II) (280 mg, 0.4 mmol) in dioxane (20 mL) was added an aqueous sodium carbonate solution (2 M, 10 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (1.3 g, 57%) as a white solid: LC/MS m/e calcd for C29H30N2O5S2 [M+H]+ 551.70, observed 551.4.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([C:35]1[CH:36]=[CH:37][C:38]([N+:48]([O-:50])=[O:49])=[C:39]([CH:41]([CH3:47])[CH2:42][O:43][C:44](Cl)=[O:45])[CH:40]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)Cl>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][C:44]([O:43][CH2:42][CH:41]([C:39]2[CH:40]=[C:35]([C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:36]=[CH:37][C:38]=2[N+:48]([O-:50])=[O:49])[CH3:47])=[O:45])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: CC(COC(=O)Cl)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(COC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 56.6 %

Procedure:
N6-benzoyl-2′-deoxyadenosine (23.63 g, 67 mmol) was dried by coevaporation with abs. pyridine (3×100 mL), dissolved in pyridine (400 mL) and cooled to 0° C. A solution of 2-(5-benzoyl-2-nitrophenyl)-1-propyl oxycarbonylchloride (19f) (35 mmol, prepared from 10.00 g of alcohol 4f) in abs. CH2Cl2 (100 mL) was added drop wise over a period of 2.5 hours. After stirring over night at ambient temperature the reaction mixture was concentrated in vacuo, dissolved in CH2Cl2 and washed with water (2×200 mL). Excess N6-benzoyl-2′-deoxyadenosine precipitated as a crystalline solid from the aqueous phase and was recovered by filtration. The organic phase was diluted with toluene (100 mL), concentrated in vacuo and purified by silica column chromatography (315 g silica, column diameter 5.5 cm, gradient: CH2Cl2 to CH2Cl2/methanol 100:5) to provide 13.20 g (19.8 mmol, 57%) of the product 29 as a slightly yellow foam. 1H-NMR (250 MHz, DMSO-d6): δ 11.02 and 11.01 (2 s, 2H, NH), 8.67 (s, 1H, H—C(2)), 8.51 and 8.50 (2 s, 2H, H—C(8)), 8.00-7.48 (m, 13H, arom.), 6.46 (m, 1H, H—C(1′)), 5.47 (d, 1H, HO—C(3′)), 4.46 (m, 1H, H—C(3′)), 4.28 (m, 4H, 2×CH2), 4.03 (m, 1H, H—C(4′)), 3.50 (m, β-CH), 2.86 (m, 1H, H—C(2″)), 2.40 (m, 1H, H—C(2′)), 1.28 (d, 3H, γ-CH3).
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5].[Br:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>CN(C=O)C>[Br:16][CH2:17][CH2:18][NH:19][C:20]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5])=[O:21]
Reactant: O=C=NCCBr
Reactant: NCCC(=O)NC(=O)c1ccccc1S
Solvent: CN(C)C=O
Product: NCCC(=O)NC(=O)c1ccccc1SC(=O)NCCBr
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of N-(2-mercaptobenzoyl)-β-alaninamide (0.90 g, 4.0 mmol) in DMF (20 ml) was added 2-bromoethyl isocyanate (0.91 g, 6.0 mmol). The reaction mixture was stirred for 6 h. The solvent was evaporated to dryness, and the residue was treated with ethyl ether (20 ml) with vigorous stirring. The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield: 87%. 1H NMR (DMSO-d6): 2.36 (t, 2H, CH2), 3.42 (q, 2H, CH2), 3.54 (s, 4H, 2CH2), 6.88 (brs, 1H, NH2), 7.36-7.66 (m, 5H, Ar—H, NH2), 8.26 (t, 1H, NH), 8.66 (brs, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][Br:32]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
5.61 g of 5-chloro-2-nitrobenzyl alcohol is mixed with 9.1 g of triphenylphosphine in 100 ml of dichloromethane. To this solution 6.1 g of N-bromosuccinimide is added portionwise over 5 minutes (to avoid foaming as the reaction warms to ca. 5° C.). After stirring 30 minutes 10 wt % of both triphenylphosphine (900 mg) and N-bromosuccinimide (600 mg) are added. After an additional 30 minutes stirring the reaction mixture is concentrated to approximately 10 ml, poured on a bed of Celite®, and then rinsed through with 0.1% methanol in dichloromethane. Evaporation of the filtrate provides 2.43 g of 5-chloro-2-nitrobenzyl bromide as a light yellow oil. 1H-NMR (500 MHz, CDC13) δ (ppm) 4.806 (s, 2H), 7.457-7.479 (dd, 1H), 7.589-7.593 (s, 1H), 8.033-8.051 (d, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[C:23]#N.CO.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[CH:23]=[O:28]
Reactant: O=S(=O)(O)O
Reactant: COc1cccc(OC)c1/C=C/C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cccc(OC)c1/C=C/C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Add 355 mL of a 1M solution of diisobutylaluminium hydride (DIBAL-H) (355 mmol) in toluene to a solution of 61 g (322 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in 600 mL of anhydrous toluene under argon and cooled to 0° C., maintaining the temperature at 0° C. Then bring the reaction mixture to room temperature (RT) and stir for 3 h. Then add 13 mL (322 mmol) of methanol and then, dropwise, 170 g (174 mmol) of an aqueous solution of sulphuric acid at 10 wt. %. Stir the suspension for one hour, then filter on a celite bed. Wash the filtrate with 500 mL of water then dry over Na2SO4 and concentrate under reduced pressure. Take up the residue obtained in 500 mL of DCM and filter in a silica column, eluting with DCM. After concentration under reduced pressure, we obtain 37 g of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde in the form of colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=2)[CH:3]=1)#[N:20]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-3-(trifluoromethyl)benzene (66 μL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from methanol to give the title compound (106 mg, 56%) as a white powder.
Reaction SMILES: C(OC([N:6]([CH2:8][CH:9]([OH:15])[CH2:10][P:11](=[O:14])([OH:13])[OH:12])[OH:7])=O)C.O.N>Cl.CO>[OH:15][CH:9]([CH2:8][NH:6][OH:7])[CH2:10][P:11](=[O:12])([OH:14])[OH:13]
Reactant: CCOC(=O)N(O)CC(O)CP(=O)(O)O
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: O=P(O)(O)CC(O)CNO
Yield: 36.7 %

Procedure:
A solution of 3-(N-ethoxycarbonyl-N-hydroxyamino)-2-hydroxypropylphosphonic acid (2.4 g.) in 1 N hydrochloric acid (100 ml.) was heated to reflux for 14 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, to which was added water (20 ml.), washed twice with chloroform (each 10 ml. portion) and decolorized with activated charcoal (200 mg.). The activated charcoal was filtered off and the filtrate was evaporated to dryness under reduced pressure to give a dark reddish oil, to which was added water (3 ml) and adjusted to pH 4.0 with 28% aqueous ammonia. This aqueous solution was diluted with methanol and allowed to stand at ambient temperature, and then the precipitating crystals were collected by filtration to give 2-hydroxy-3-(N-hydroxyamino)propylphosphonic acid (0.62 g.).