Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:11]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:11]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)C(CC1CCC1)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(CC1CCC1)c1ccc(N)c(OCC(F)(F)F)c1
Yield: 103.1 %

Procedure:
A solution of the 3-cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid methyl ester (15 g, 36.0 mmol) in EtOH (150 mL) was hydrogenated at 50 psi and 25° C. for 16 h in the presence of Pd—C catalyst (10%, 1.5 g). On the next day, the catalyst was filtered off and the solvent evaporated to give the crude product (12.3 g, 88%) as a yellow oil, which was used without purification for the next step. 1H NMR (300 MHz, CDCl3/TMS): δ 6.79-6.73 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 4.36 (q, J=8.3 Hz, 2H), 3.80 (br s, 2H), 3.63 (s, 3H), 3.35 (t, J=7.7 Hz, 1H), 2.20-1.86 (m, 4H), 1.85-1.70 (m, 3H), 1.67-1.51 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.7, 146.7, 135.7, 129.1, 123.3 (d, 1JCF=277.6 Hz), 122.7, 115.4, 112.2, 66.4 (q, 1JCF=35.4 Hz), 51.9, 48.9, 40.8, 34.0, 28.3, 28.1, 18.5.
Reaction SMILES: [C:1](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:21]([O:28][C:29]1[CH:48]=[CH:47][C:46]([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:45][C:30]=1[C:31]([NH:33][C:34]1[CH:43]=[C:42]([Br:44])[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][C:29]1[CH:48]=[CH:47][C:46]([CH:49]2[CH2:54][CH2:53][N:52]([CH3:1])[CH2:51][CH2:50]2)=[CH:45][C:30]=1[C:31]([NH:33][C:34]1[CH:43]=[C:42]([Br:44])[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.12 mL), a 37% aqueous solution of formaldehyde (0.10 mL), and sodium triacetoxyborohydride (0.54 g) were sequentially added to a tetrahydrofuran (5.4 mL) solution of the obtained methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-bromobenzoate (0.54 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.48 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-bromobenzoate as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[N:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[N:5]=1
Reactant: [H][H]
Reactant: O=C1NC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccn(C[C@@H]2CNC(=O)O2)n1
Yield: 1.1 %

Procedure:
In a Parr shaker bottle was placed (S)-5-(3-nitro-pyrazol-1-ylmethyl)-oxazolidin-2-one (364 mg, 1.72 mmol), 10% palladium on carbon (200 mg) and ethanol (25 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 4 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentrated in vacuo to afford (S)-5-(3-amino-pyrazol-1-ylmethyl)-oxazolidin-2-one (3.60 mg, 91%) as a yellow oil: LR-ES-MS m/z calculated for C7H10N4O2 [M]+ 182, observed 183 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:46]1([O:51][C:52](=[O:62])[C@H:53]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58]C=2)[NH2:54])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:54][C@@H:53]([C:55]3[CH:56]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:52]([O:51][CH:46]3[CH2:47][CH2:48][CH2:49][CH2:50]3)=[O:62])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OCCCN[C@H](C(=O)OC2CCCC2)c2ccccc2)cc1F

Procedure:
From Intermediate 4E and L-phenylalanine cyclopentyl ester tosylate salt (Intermediate 16), LCMS purity 97%, m/z 634 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.30-2.00 (8H, m), 2.30 (2H, m), 3.10 (1H, m), 3.40 (1H, m), 4.25 (2H, m), 4.40 (1H, m), 5.20 (1H, m), 5.85 (1H, d), 6.90 (2H, m), 7.10 (2H, d), 7.20-7.45 (7H, m), 7.65 (2H, m), 7.75 (1H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:31][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[CH:17]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:32])[CH2:3]1.C(N(CC)CC)C.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C(O[C:60]([NH:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1)=O)(C)(C)C.[H-].[Na+].IC>C(Cl)Cl.O>[CH3:1][C:2]1([CH3:33])[CH2:31][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:65]5[CH2:66][CH2:67][C@@H:63]([NH:62][CH3:60])[CH2:64]5)=[O:26])[CH:23]=4)[CH:17]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:32])[CH2:3]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(C(=O)O)c4)c3)c2C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: On1nnc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CI
Product: CN[C@@H]1CCN(C(=O)c2cccc(-c3cc(-c4c(N5CCOCC5)sc5c4CC(C)(C)CC5=O)ccn3)c2)C1
Reaction time: 18 h
Yield: 10.4 %

Procedure:
To a solution of Example 254 (300 mg, 0.44 mmol) in DCM (20 mL) was added triethylamine (0.6 mL, 4.35 mmol), EDC (334 mg, 1.74 mmol) and 1-hydroxybenzo-triazole (10 mg, 0.09 mmol) and the reaction mixture was stirred at room temperature for 2 h. (3R)-(+)-3-(tert-Butoxycarbonylamino)pyrrolidine (323 mg, 1.74 mmol) was then added and stirring was continued at room temperature for 18 h. Water (30 mL) was added and the mixture was extracted into DCM (100 mL). The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane). The obtained solid was taken up in DMF (5.0 mL) and sodium hydride (60% dispersion in oil, 14 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, then iodomethane (20 μL, 0.36 mmol) was added and stirring was continued for 1 h. Water (20 mL) was added and the reaction mixture was extracted with EtOAc (80 mL). The organic phase was washed with water (6×20 mL) and brine (20 mL), then dried (magnesium sulfate). The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane). The obtained solid was taken up in DCM (5.0 mL) and trifluoroacetic acid (1.0 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and the solvent was removed in vacuo. The residue was purified by preparative HPLC (pH 5.8) and the obtained product was partitioned between sodium hydrogencarbonate solution (20 mL) and DCM (2×75 mL). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (25 mg, 8%) as an off-white solid. δH (CD3OD) 8.75 (1H, d, J 5.1 Hz), 8.28-8.13 (2H, m), 8.01 (1H, s), 7.69-7.60 (2H, m), 7.51-7.45 (1H, m), 3.88-3.50 (7H, m), 3.41-3.22 (2H, m), 3.14-3.02 (4H, m), 2.64 (2H, s), 2.46 (3H, 2×s), 2.33 (2H, s), 2.30-2.06 (1H, m), 1.98-1.80 (1H, m), 1.05 (6H, s). LCMS (ES+) 545.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]=[O:20])=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10]>C(O)(=O)C>[OH:20][C:19]1[C:4]([C:5](=[O:7])[CH3:6])=[N:3][N:2]([CH3:1])[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: CC(C)Cc1ccc(C(=O)C=O)cc1
Reactant: CNN=CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 4.9 %

Procedure:
2-Oxopropanal methylhydrazone (11.60 mmol, 1.16 g) and (4-isobutylphenyl)(oxo)acetaldehyde (11.60 mmol, 2.21 g) synthesized in Reference Synthetic Example 15 were dissolved in acetic acid (38 mL) and stirred at 100° C. for 4.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1), then by silica gel thin layer chromatography (chloroform) and by silica gel thin layer chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as a brown solid (154 mg, yield 50).
Reaction SMILES: C([O:4][P:5]([CH2:11][O:12][CH2:13][C:14]([CH2:37][CH3:38])=[CH:15][CH2:16][C:17]1[C:18]([O:30]CC[Si](C)(C)C)=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])(=[O:10])[O:6]C(C)C)(C)C.N1C(C)=CC=CC=1C.Br[Si](C)(C)C>C(#N)C>[CH2:37]([C:14](=[CH:15][CH2:16][C:17]1[C:18]([OH:30])=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])[CH2:13][O:12][CH2:11][P:5](=[O:4])([OH:6])[OH:10])[CH3:38]
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)COCP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: CCC(=CCc1c(O)c2c(c(C)c1OC)COC2=O)COCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of {2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonic acid diisopropyl ester (347 mg, 0.61 mmol) in acetonitrile (5 mL) was added 2,6-lutidine (0.71 mL, 6.1 mmol) and bromotrimethylsilane (0.786 mL, 6.1 mmol). The mixture was stirred at room temperature for 3 hours, quenched with methanol (5 mL), concentrated, and partitioned between ethyl acetate and 1N HCl (aqueous). The organic layer was concentrated to give the free phosphonic acid as a colorless oil (205 mg, 70%). This material (20 mg) was dissolved in a solution of trifluoroacetic acid (0.3 mL) and dichloromethane (2.7 mL) and stirred for 30 minutes at ambient temperature. After concentration, the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide the product, after lyophilization, as a white solid (10 mg). 1H NMR (300 MHz, CDCl3) δ 1.007 (t, 3H, J=7.5 Hz), 2.13 (s, 3H), 2.32 (q, 2H, J=7.5 Hz), 3.41 (d, 2H, J=6.3 Hz), 3.56 (d, 2H, J=9 Hz), 3.75 (s, 3H), 3.95 (s, 2H), 5.16 (s, 2H), 5.43 (t, 1H, J=6.3 Hz) ppm; 31P (121.4 MHz, CDCl3) δ 22.8 ppm; MS (m/z) 385.2 [M−H]+, 387.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@H:19](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]([NH:48][C:49]1[CH:54]=[CH:53][NH:52][C:51](=[O:55])[N:50]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.ClCCl.C(OCC)(=O)C>[C:8]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@@H:19]([N:52]3[CH:53]=[CH:54][C:49]([NH:48][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:50][C:51]3=[O:55])[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A reaction mixture containing the trans-D tosylate (7) (1.10 g, 2.00 mmol), N4-benzoylcytosine (0.475 g, 2.20 mmol), anhydrous K2CO3 (0.300 g, 2.20 mmol) and 18-crown-6 (200 mg) in DMF (10 ml) was stirred at 70-80° C. under argon overnight. The white suspension was diluted with dichloromethane (75 ml), filtered through celite and the organic phase washed with water. Evaporation gave the crude product as an oil which was purfied by column chromatography (SiO2, ethyl acetate). The more polar fractions (Rf 0.33) were combined and evaporated to give the N1-isomer (0.299 g, 25%) as a white foam. Recrystallisation from ethanol-water gave white crystals of N-tert-butoxycarbonyl-cis-4-(N4-benzoylcytosin-1-yl)-D-proline diphenylmethyl ester (11), m.p. 133-135° C., (Found C, 65.8; H, 6.5; N, 8.8%; C34H34N4O6. C2HR5OH.H2O requires C, 65.6; H, 6.4; N, 8.5%), δH (200 MHz; CDCl3) 1.30 and 149 (9H, 2xs, Boc rotamers), 2.20 and 2.90 [2H, br m, CH2(3′)], 3.50-3.80 and 3.95-4.15 [2H, 2xbr m, CH2(5′)], 445-4.70 [1H, br m, CH(2′)], 5.28 [1H, br m, CH(4′)], 6.87 (1H, s, CHPh2), 7.15-7.40 (10H, m, phenyl CH), 7.40-7.75 [5H, m, CH(5), CH(6) and benzoyl m- and p-CH], 7.89 (2H, d, J=7.4 Hz, benzoyl o-CH), 8.83 (1H, br s, NH); δC (50.28 MHz; CDCl3) 27.7 and 28.0 (Boc CH3 rotamers), 34.4 and 36.0 [CH2(3′) rotamers], 49.6 and 50.5 [CH2(5′) rotamers], 54.3 and 54.9 [CH(4′) rotamers], 57.6 CH(2′)], 78.0 and 78.3 (CHPh2 rotamers), 81.3 (Boc C), 96.8 [CH(5)], 127.0-129.2 (aromatic CH), 133.4 (benzoyl C), 139.5 (aromatic C), 145.2 and 145.7 [CH(6) rotamers)], 153.8 (Boc CO rotamers), 155.6 [C(2)], 162.0 [C(4)], 166.8 (benzoyl CO), 171.3 (ester CO); m/z (ES MS) 595 (M+H+, 100%); νmax (KBr)/cm−1 1743 (C═O), 1704s (C═O); λmax (CHCl3)/nm 266 (ε/dm3.mol−1.cm−1 8.9×104), 312 (3.4×104); [α]D25 −13.6 (c=0.50, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>[I-].[Na+].CC(=O)CC>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1cc(C(=O)OC)ccc1OC
Yield: 71 %

Procedure:
A mixture of 45 g of product from Example 40, 51.2 g of finely powdered potassium carbonate, 72 g of 1-bromotetradecane, 1.9 g of sodium iodide and 500 ml of 2-butanone is heated at reflux temperature for 18 hours under an atmosphere of argon. The reaction is cooled and filtered. The filtrate is concentrated in vacuo and the residue is dissolved in chloroform. The organic layer is washed with 1N sodium hydroxide and saturated sodium chloride, dried and concentrated in vacuo. The residue is recrystallized from hexane to give 66.4 g of the desired product as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH:8]([C:12]([O:14]C)=O)[C:7]2=O.[NH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[NH2:18].C(O)(=O)C>C(OCC)(=O)C>[F:1][C:2]1[C:11]2[S:10][CH:9]=[C:8]3[C:12](=[O:14])[N:17]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=4)[N:18]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CSc2c(F)cccc2C1=O
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1

Procedure:
Methyl 8-fluoro-4-oxothiochromane-3-carboxylate (1.19 g, 4.95 mmol) and 4-hydrazinobenzoic acid (755 mg, 4.95 mmol) were mixed with glacial acetic acid (10 ml). The mixture was heated to reflux for 4 h. Excess acetic acid was removed under vacuum to give an orange oil. Ethyl acetate (10 ml) was added and the mixture sonicated. Precipitation of an orange solid was observed. The solids were collected by filtration and washed with ethyl acetate. The filter cake was taken up in dimethyl suphoxide (10 ml) and air-oxidised at room temperature for one week. Water (20 ml) was added to the reaction mixture, the solids were collected by filtration, slurried in ethyl acetate, filtered and dried under vacuum. The title compound was isolated as an orange powder (175 mg, 0.51 mmol, 10%). LCMS: m/z 341.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: CNC(=O)c1ccccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F

Procedure:
Method B was applied to a mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (103 mg, 0.34 mmol), 2-amino-N-methylbenzamide (51 mg, 0.34 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), xantphos (28 mg, 0.014 mmol) and cesium carbonate (234 mg, 0.72 mmol) in dioxane (4.5 ml).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([N:61]=[N:62][C:63]2[CH:76]=[CH:75][C:66]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]O)=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53].O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][O:67][C:66]2[CH:65]=[CH:64][C:63]([N:62]=[N:61][C:58]3[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:60][CH:59]=3)=[CH:76][CH:75]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(OCCCCCCO)cc2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCCCCCCOc3ccc(N=Nc4ccc([N+](=O)[O-])cc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
0.2 g of N,N'-dicyclohexyldicarbodiimide (DCC) was added at room temperature while stirring to a solution of 0.5 g of 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoic acid, 0.25 g of 6-[4-(4-nitrophenylazo)phenoxy]hexanol and 0.04 g of 4-dimethylaminopyridine (DMAP) in 25 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol 1:1) and two-fold recrystallization from acetone of the fractions which were pure according to thin-layer chromatography gave 0.4 g of 6-[4-(4-nitrophenylazo)phenoxy]hexyl 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoate; m.p. (C-N) 72° C., cl.p. (N-I) 127° C.
Reaction SMILES: C(C1N=C(N2CCOCC2)[C:8]2N=N[N:11]([CH2:14][C:15]3[CH:20]=CC=C[C:16]=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].CC1(C)CCNC1>>[C:28]([C:32]1[N:33]=[C:34]([N:11]2[CH2:9][CH2:8][C:15]([CH3:16])([CH3:20])[CH2:14]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1(C)CCNC1
Product: CC1(C)CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-dimethylpyrrolidine. MS (m/e): 399.4 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:8][C:7]=1[S:26]([NH-:29])(=[O:28])=[O:27].N1C=CC=CC=1.[C:36](Cl)(Cl)=[O:37]>ClCCCl>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:8][C:7]=1[S:26]([N:29]=[C:36]=[O:37])(=[O:27])=[O:28]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S([NH-])(=O)=O)c(Cl)cc2F)c1=O
Reactant: O=C(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)N=C=O)c(Cl)cc2F)c1=O
Temperature: 60 °C

Procedure:
At 60° C., 7.4 g (62.3 mmol) of thionyl chloride were added dropwise with stirring to a suspension of 10.0 g (24.9 mmol) of 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]-benzenesulfonylamide in 1,2-dichloroethane. The mixture was then boiled under reflux for 4 h. The mixture was then cooled to 60° C., a catalytic amount of pyridine was added and phosgene was introduced under reflux for 12 h until a clear solution was obtained. After cooling to 30° C., the product was freed from the solvent. This gave 11.6 g (98% of theory) of the title compound.