Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].COC1C=CC(C[N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][N:24]([C:28](=[O:37])[C@H:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH3+:30])[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=CC=1.[CH3:40][O:41][C:42]1[CH:78]=[CH:77][C:45]([CH2:46][N:47]2[C:51]3[N:52]=[CH:53][C:54]4[CH2:55][N:56]([C:60](=[O:76])[C@@H:61]([NH:68]C(=O)OC(C)(C)C)[C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)[CH2:57][CH2:58][C:59]=4[C:50]=3[CH:49]=[N:48]2)=[CH:44][CH:43]=1.[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH:17]1[C:18]2[C:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:37])[C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH3+:30])[CH2:23][C:22]=3[CH:21]=[N:20][C:19]=2[NH:15][N:16]=1.[F:79][C:80]([F:85])([F:84])[C:81]([O-:83])=[O:82].[CH3:40][O:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[C:51]3[N:52]=[CH:53][C:54]4[CH2:55][N:56]([C:60](=[O:76])[C@H:61]([C:62]5[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=5)[NH3+:68])[CH2:57][CH2:58][C:59]=4[C:50]=3[CH:49]=[N:48]2)=[CH:77][CH:78]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)CC4)cc1
Agent: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)[C@@H]([NH3+])c2ccccc2)CC4)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: [NH3+][C@H](C(=O)N1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Synthesis of (S)-2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate. To a solution of (S)-tert-butyl 2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethylcarbamate (0.23 g, 0.43 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude product was purified using reverse phase HPLC to give the pure desired product (S)-2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate as a pale yellow solid (0.131 g, 50%). M.p.>115° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (brs, 2H), 8.45/8.15 (s, 1H, rotamers), 8.12/8.08 (s, 1H, rotamers), 7.55-7.33 (m, 5H), 7.17 (m, 2H), 6.82 (m, 2H), 5.75 (m, 1H), 5.55 (s, 2H), 4.97-4.35 (m, 2H), 4.02/3.74 (m, 2H, rotamers), 3.01/2.30 (m, 2H, rotamers); LC-Mass: m/e 428.57 (M+H). LCMS [M+H]: 428.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].C(N(CC)CC)C.[F:16][C:17]([F:23])([F:22])[S:18](F)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:16][C:17]([F:23])([F:22])[S:18]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:20])=[O:19]
Reactant: OCC(F)(F)C(F)F
Reactant: O=S(=O)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reaction time: 0.75 h

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (244.3 g, 1.85 mol, obtained from Sinochem Corp.), triethylamine (187.2 g, 1.85 mol, obtained from Aldrich Chemical Co.) and 500 mL of chloroform were combined in a 2-liter Parr pressure reactor and sealed. The reactor temperature was set to −10° C. Trifluoromethanesulfonyl fluoride (281.33 g, 1.85 mol, obtained from 3M Company) was added at such a rate that the temperature did not exceed −5° C. Once the addition was complete, the mix was held at −10° C. for 45 minutes. The reaction mix was then emptied and washed with 2×500 mL portions of water and 1×250 mL portion of 1N HCl. GC analysis of the reaction mixture indicated a 97 percent conversion to the product. The chloroform solvent was removed by rotary evaporation. The product was dried over anhydrous magnesium sulfate which was then filtered from the product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:9])=[CH:5][CH2:6][CH2:7][OH:8].Br[CH2:11][CH2:12][CH2:13][C:14]1([O:19][CH2:18][CH2:17][O:16]1)[CH3:15].O>CN(C)C=O>[CH2:17]1[CH2:18][O:19][C:14]([CH2:13][CH2:12][CH2:11][O:8][CH2:7][CH2:6][CH:5]=[C:4]([CH3:9])[CH3:3])([CH3:15])[O:16]1
Reactant: CC1(CCCBr)OCCO1
Reactant: CC(C)=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCOCCCC1(C)OCCO1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
14 g of sodium hydride in a 50% suspension in oil were added to a solution of 28 g of 4-methyl-3-pentenol [Julia et al, Bull. Soc. Chim., (1960), p. 1072] in 250 ml of dimethylformamide and after stirring the mixture for 1 hour, 66 g of 5-bromo-2,2-ethylenedioxy-pentane were added thereto while keeping the temperature below 35° C. The mixture was stirred at room temperature for 17 hours and the reaction mixture was then poured into water. The mixture was extracted with petroleum ether (b.p.= 40°-75° C.) and the organic phase was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was rectified to obtain 20 g of 2,2-ethylenedioxy-10-methyl-6-oxa-9-undecene in the form of a colorless liquid with a boiling point of 75° C. at 0.05 mm Hg.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=2[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]1([CH:7]([NH:9][C:10]2[CH:15]=[C:14]([N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]3)[CH:13]=[CH:12][C:11]=2[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Yield: 30.5 %

Procedure:
1-(2-(1-Phenylethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (150 mg, 0.48 mmol), t-butyl piperazine-1-carboxylate (98.7 mg, 0.53 mmol), N,N-diisopropylethylamine (124 mg, 0.96 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 21 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (70 mg, 30% yield). 1H NMR (400 MHz, CDCl3): δ 9.36 (d, 1H), 7.60 (d, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 6.13 (d, 1H), 5.61 (s, 1H), 4.55 (m, 1H), 3.41 (m, 4H), 3.25 (m, 2H), 3.14 (m, 2H), 1.61 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C25H30F3N3O3: 477.22; Observed: 500.3 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N+:14]([O-])[O:15][N:16]=2)[C:5]2[N:6]=[C:7]([OH:13])[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.P(OCC)(OCC)OCC>C(O)C.CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4](=[N:14][O:15][N:16]=2)[C:5]2[N:6]=[C:7]([OH:13])[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: [O-][n+]1onc2c(Cl)cc3nc(O)c(O)nc3c21
Agent: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: CCO
Product: Oc1nc2cc(Cl)c3nonc3c2nc1O
Yield: 69.9 %

Procedure:
To a solution of 0,6 g (2,4 mmol) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide in a mixture of 14 ml ethanol and 3 ml dimethylformamide was added 0.9 ml (5,3 mmol) triethyl phosphite. The mixture was refluxed for 4 h, and then evaporated in vacuo. The residue was stirred with water and then with ether-ethyl acetate (5:1) to give 0,4 g (71%) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo-(3,4-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6 +D2O): 7.40 (lH,s).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>O>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of toluene (70 mL) and water (10 mL) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (3.2 g, 30.43 mmol), 4-bromobenzaldehyde (2.0 g, 10.6 mmol), 4-trifluoromethoxyphenylboronic acid (2.86 g, 13.95 mmol) and tetrakis triphenyl phosphene palladium(0) (1.0 g, 1.562 mmol) were added to the above degassed water/toluene mixture. The reaction mixture refluxed overnight. After the reaction is completed, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ (ppm)=7.2-8.0 (m, 8H), 10.0 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=O)[CH:28]=[CH:27][C:25]=2[N:26]=1.CCOP(O)N(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]3[O:8][C:7]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:11][CH:10]=4)=[N:34][N:33]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cn1
Temperature: 150 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
6-Trifluoromethyl-nicotinoyl chloride (119 uL, 0.817 mmol) was added to a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol) in THF (10 mL) and EDIPA (149 uL, 0.856 mmol). The reaction was stirred for 17 hr. The reaction was diluted with EtOAc (75 mL) and extracted with water (20 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was taken up in DMF (3 mL) and transferred to a microwave vial charged with Burgess reagent (555 mg, 2.33 mmol). The reaction was heated to 150° C. for 15 min by microwave irradiation. The reaction was diluted with EtOAc (75 mL) and extracted with water (15 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (15-40% ACN/DCM) and the resulting colorless film triturated with MeOH/DCM to afford the title compound (214 mg): 1H NMR (400 MHz, DMSO-d6) ppm 7.64-7.68 (m, 1 H) 7.71 (s, 1 H) 7.73 (d, J=2.02 Hz, 1 H) 7.83 (tautomer, d, J=8.46 Hz, 1 H) 7.97 (tautomer, d, J=8.59 Hz, 1 H) 8.12 (dd, J=14.15, 8.72 Hz, 1 H) 8.21 (d, J=8.34 Hz, 1 H) 8.41 (tautomer, s, 1 H) 8.60 (tautomer, s, 1 H) 8.85 (d, J=8.34 Hz, 1 H) 9.54 (s, 1 H) 13.41 (d, J=14.15 Hz, 1H); LCMS tR=1.53 min, MS (m/z) 476.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>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(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1ccccc1
Yield: 80 %

Procedure:
Microwave vial was charged with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (100 mg, 0.376 mmol), phenylboronic acid (2 eq), Cs2CO3 (3 eq), Pd(PPh3)2Cl2 (0.08 eq), DME (1 ml), and ethanol (0.25 ml). The vial was irradiated in microwave synthesizer at 140° C. for 20 min. The contents of the vial were filtered through a celite pad, which was washed out thoroughly with methanol. The filtrate was evaporated, and the residue was purified by column chromatography to give 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (96 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[CH:48]=[C:49]([CH:53]2[CH2:67][N:57]3[C:58](=[O:66])[NH:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][C:65]=4[C:56]3=[N:55][CH2:54]2)[CH:50]=[CH:51][CH:52]=1>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH:53]2[CH2:67][N:57]3[C:58](=[O:66])[NH:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][C:65]=4[C:56]3=[N:55][CH2:54]2)[CH:48]=1)=[O:9]
Reactant: Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccoc1C(=O)Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of 3-methyl-furan-2-carboxylic acid (2.4 mg, 0.019 mmol), N,N-diisopropylethylamine (0.017 mL, 0.095 mmol), and BOP (10.1 mg, 0.023 mmol) in 0.6 mL DMF was stirred at rt for 1 hour, then 3-(3-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (5.0 mg, 0.017 mmol) added and the reaction continued at rt. After 2.5 hours, a small spatula tip of 3-methyl-furan-2-carboxylic acid and BOP was added and the reaction heated at 60° C. for 1 hour. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The residue was rinsed with 2 portions of 30% EtOAc/hexane and then chromatographed eluting with 10% MeOH/CHCl3. The resulting solid was chromatographed using a prep plate and eluting with 50% acetone/hexane. The obtained solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and evaporated to give the title compound as a white solid (3.2 mg, 47%). 1H NMR (CD3OD/CDCl3 mixture) δ: 8.04 (dd, J=8.2, 1.2 Hz, 1H), 7.68 (t, J=1.8 Hz, 1H), 7.60 (ddd, J=8.1, 2.1, 0.9 Hz, 1H), 7.46-7.53 (m, 2H), 7.37 (t, J=7.9 Hz, 1H), 7.16 (ddd, J=8.1, 7.2, 1.2 Hz, 1H), 7.03-7.10 (m, 2H), 6.45 (dd, J=1.8, 0.6 Hz, 1H), 4.48-4.56 (m, 1H), 3.86-3.95 (m, 1H), 3.61-3.74 (m, 2H), 3.07-3.19 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][C@@H:4]([C:16]([NH2:18])=[O:17])[CH2:3]1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C>[C:12]([O:11][C:9]([NH:8][C@@H:7]1[CH2:6][CH2:5][C@@H:4]([C:16](=[O:17])[NH2:18])[CH2:3][C@@H:2]1[O:1][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@H]1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To (1R,3R,4R)-3-hydroxy-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid amide (e) (2.78 g, 10.8 mmol), para-nitrobenzoic acid (2.16 g, 12.9 mmol) and triphenylphosphine (3.38 g, 12.9 mmol) in dry THF (200 mL) and DMF (25 mL) under argon was added dropwise diisopropyl azodicarboxylate (2.5 mL, 12.9 mmol) at 0° C. After 5 min at 0° C. and 17 hours at room temperature, the mixture was concentrated in vacuo and the residue purified by flash column chromatography (silica gel, DCM/MeOH, 0-4%) to give a white solid (2.36 g, 5.8 mmol, 54%).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[F:1][CH:2]([F:5])[CH2:3][O:4][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 2,2-difluoro-ethanol (6 g, 73.12 mmol) and mesyl chloride (6.26 ml, 80.43 mmol) in CH2Cl2 (40 ml) was added triethylamine (12.66 ml, 87.74 mmol) dropwise at 0° C. After the addition was completed, the mixture was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was then washed two times with water and with brine and dried with Na2SO4. Evaporation of the solvent yielded the title compound (10.7 g, 92%) as yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)(O)[O-].[Na+].CO.ClCCl.[I:19](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:19])[NH2:5]
Reactant: O=I(=O)Cl
Reactant: Nc1cccc(F)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(I)c(F)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1 methanol-dichloromethane (20 mL) at 0° C. was added a solution of benzyl trimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) over 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour. The mixture was quenched by addition of water and the organic layer was extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (2.20 g, 89%) as a pink solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.41 (dd, J=8.3, 7.3 Hz, 1H), 6.42 (dd, J=9.9, 2.5 Hz, 1H), 6.27 (dd, J=8.5, 2.5 Hz, 1H), 3.81 (s, 2H); MS+ESI m/z (rel abundance) 238 (100, M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[OH:21])=[O:11])[CH3:8].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[O:21][CH2:28][C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1oc2ccncc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccncc2c1OCc1ccccc1
Reaction time: 0.08 h

Procedure:
K2CO3 (2.34 g, 17.0 mmol) was added to a stirred solution of 3-hydroxyfuro[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.76 g, 8.5 mmol) in DMF (40 mL). After 5 min, BnBr (1.25 mL, 10.6 mmol) was added, then the mixture was stirred for 16 h, before being poured into H2O and extracted with EtOAc (3×). The combined organic extracts were washed with brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc) yielded the title compound: m/z (ES+)=298.0 [M+H]+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[CH2:23](O)[CH2:24][CH3:25].O>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: CCCO
Reactant: O=C(O)c1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
CDI (2.34 g, 14.48 mmol) was added to a solution of salicylic acid (2.00 g, 14.48 mmol) in DMF (40 mL). The reaction mixture was stirred at 50° C. for 4 h and PrOH (2.72 mL, 36.20 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into H2O (20 mL) and extracted with Et2O (2×40 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 2.05 g of propyl 2-hydroxybenzoate (colourless oil, yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cu](C#N)[C:13]#[N:14].Cl>CN1CCCC1=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:13]#[N:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N#C[Cu]C#N
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(C(=O)O)c1
Temperature: 190 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A solution of 2-amino-5-bromobenzoic acid (6.9 g, 31.9 mmol) in N-methyl-2-pyrrolidinone (100 mL) was treated with copper cyanide (4.14 g, 46 mmol) and the mixture was heated at 190° C. for 4.5 hours before being cooled to room temperature and allowed to stand overnight. The mixture was diluted with water (500 mL), acidified with 6N aqueous HCl (100 mL) and extracted with ethyl acetate (6×40 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield the crude nitrile (4.35 g, 84%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][C:30]1([F:41])[O:34][C:33]2[CH:35]=[CH:36][C:37]([CH2:39]O)=[CH:38][C:32]=2[O:31]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:39][C:37]2[CH:36]=[CH:35][C:33]3[O:34][C:30]([F:41])([F:29])[O:31][C:32]=3[CH:38]=2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: O=c1[nH]nc(Br)c(=O)[nH]1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]nc(Br)c(=O)n1Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Yield: 20.4 %

Procedure:
According to Scheme 2 Step 2: A mixture of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione 2(A) (943 mg, 4.91 mmol), CH2Cl2 (40 mL), triphenylphosphine (1.76 g, 6.69 mmol), (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (840 mg, 4.46 mmol) was stirred at 0° C. under nitrogen atmosphere. Di-tertbutyl azodicarboxylate (2.05 g, 8.93 mmol) was added portionwise and the mixture was stirred for 16 hours at room temperature. 200 mL of water were added and the aqueous layer was extracted thrice with 200 mL of DCM. The organic layers were combined and were successively dried over MgSO4, filtered and concentrated under reduce pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column SiO2) using AcOEt/cyclohexane 3/7 as eluant to afford 6-bromo-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione 5(A) (330 mg, 20%) as a white solid.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]>>[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH2:7])=[O:42])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]
Reactant: COc1ccc(CN2CCN(c3nc(C)c(C(=O)O)s3)C2=O)cc1F
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: COc1ccc(CN2CCN(c3nc(C)c(C(N)=O)s3)C2=O)cc1F

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 2-(3-(3-fluoro-4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 182-184° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.31 (br, 2H), 7.20-7.07 (m, 3H), 4.37 (s, 2H), 4.03-3.97 (m, 2H), 3.82 (s, 3H), 3.48-3.42 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 365.2 (M+1).