Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@@H:5]([NH:23][C@H:24]1[C:33]2[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([C@H:5]3[CH2:4][CH2:3][CH2:2][N:23]3[C@H:24]3[C:33]4[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of (1R)-1-[[(1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl) butyl]amino]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (2.6 g) in CH2Cl2 (50 ml) was added SOCl2 (3 ml). After being stirred for 12 hours, the solvent was removed. The residue was dissolved in N,N-dimethylformamide (DMF) (15 ml) and K2CO3 (2 g) was added to the solution. After being stirred for 4 hours at the room temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.22 g). MS (m/z): 675 (M+) IR (Neat): 1560 cm-1NMR (CDCl3, δ): 1.75 (9H, s), 1.5-2.4 (8H, m), 2.7-3.2 (4H, m), 4.0-4.3 (2H, m), 6.15 (1H, d, J=8 Hz), 6.45 (1H, t, J=8 Hz), 6.92 (1H, d, J=8 Hz), 7.2-7.8 (20H, m)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:11]1([C:10]#[C:9][CH2:8][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCC#Cc1ccccc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)CN1CCNCC1
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of piperazine (862 mg, 10.0 mmol) in THF (16 mL) is added (3-bromoprop-1-ynyl)-benzene (245 mg, 1.26 mmol), and the reaction mixture is stirred overnight. THF is evaporated, water/Na2CO3 is added, the mixture is extracted with Et2O (6×10 mL), the combined extracts are washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue is purified by chromatography (silica gel, MeOH/CH2Cl2), yielding 179 mg (0.892 mmol, 71%) of the target compound. 1H NMR (CDCl3, 200 MHz): δ=1.97 (s, 1H), 2.63 (m, 4H), 2.97 (m, 4H), 3.51 (s, 2H), 7.25-7.35 (m, 3H), 7.40-7.48 (m, 2H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=2)[C:6](=[O:24])[C:7]2[CH:13]=[CH:12][C:11]([NH:14]CC3C=CC(OC)=CC=3)=[N:10][C:8]=2[N:9]=1)[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[NH2:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6](=[O:24])[N:5]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:29][CH:30]=3)[C:4]([S:3][CH2:1][CH3:2])=[N:9][C:8]=2[N:10]=1
Reactant: CCSc1nc2nc(NCc3ccc(OC)cc3)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCSc1nc2nc(N)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Yield: 60 %

Procedure:
2-(Ethylsulfanyl)-7-[(4-methoxybenzyl)amino]-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (63 mg) and anisole (26 μl) were added to trifluoroacetic acid (1 ml), and the mixture was heated under reflux for 1 hr and 30 min. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (29 mg) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[C:16](OC)[C:4]=2[N:3]1[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(OC([N:33]1C[C@H](O)C[C@H]1CO[Si](C(C)(C)C)(C)C)=O)C=C>C(Cl)(Cl)Cl>[NH2:33][C:15]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:2]([OH:1])[N:3]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:26])[Cl:25])=[O:20])[C:4]=2[CH:16]=1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: COc1cccc2c1N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc2c(c1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O

Procedure:
The protected carbinolamine 149 (0.8 g, 1.3 mmol) was added to a 5% solution of piperidine in CH3CN (12 mL, 5 eq. of piperidine). The mixture was allowed to stir for 12 hours, extracted with water (2×50 mL) and the organic phase was evaporated under reduced pressure to yield a pale yellow oil (0.24 g, 50%): 1H NMR (270 MHz, CDCl3) δ1.9-2.2 (m, 4H); 3.45-3.7 (m, 3H); 4.26 (d, J=12.1 Hz, 1H); 4.55 (m, 3H); 5.18 (d, J=12.1 Hz, 1H); 5.61 (d, J=10.3 Hz, 1H); 6.61 (s, 1H); 6.69 (d, J=7.3 Hz, 1H); 7.56 (d, J=8.2 Hz, 1H). 13C NMR (67.8 MHz, CDCl3) δ23.0; 28.7; 46.3; 59.8; 74.9; 95.1; 114.8; 116.5; 130.4; 135.3; 154.4; 167.3. IR (Nujol): cm−1 3340, 3224, 3000-2800, 1714, 1602, 1460, 1311, 1208, 1141, 1061, 826, 759, 665. MS: m/e (relative intensity) 407 (M+. , 40), 381 (5), 340 (10), 309 (25), 161 (100), 134 (15), 105 (15), 70 (80). HRMS Calculated for C15H16C13N3O4. 407.0206. Found: 407.0206. [α]25D=+47.8° (c=0.5, CHCl3).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1.C1C(=O)N([Br:30])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:22][C:3]1[C:2]([F:1])=[C:11]2[C:6]([C:7]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(C)c(F)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(CBr)c(F)c2n1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
After degassing with N2, a mixture of methyl 8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate (7-17, 169.2 mg, 0.57 mmol), NBS (106 mg, 0.59 mmol) and benzoyl peroxide (13.7 mg, 0.057 mmol) in CCl4 (2.8 ml) was stirred at 80° C. After 5 h, the solvent was removed and the residue was partitioned between EtOAC and sat. NaHCO3. The organic layer was washed with water, dried over Na2SO4 and filtered. Concentration afforded the crude methyl 7-(bromomethyl)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate, which was used without further purification (7-18). LRMS m/z (M+H)+ 378.2 found, 378.0 required.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH2:9][CH:8]1[CH2:26][CH2:27][OH:28]>ClCCl.N1C=CC=CC=1>[CH3:4][S:1]([O:28][CH2:27][CH2:26][CH:8]1[CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH:23]([CH3:24])[CH3:25])[CH:14]=2)[CH2:11][CH2:12][N:7]1[CH3:6])(=[O:3])=[O:2]
Reactant: CC(C)Oc1cc(N2CCN(C)C(CCO)C2)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1cc(N2CCN(C)C(CCOS(C)(=O)=O)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 microliters of mesyl chloride are added to a solution of 160 mg of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethanol in 2 ml of dichloromethane and 0.2 ml of pyridine. The reaction medium is stirred at ambient temperature overnight and then concentrated under vacuum, under reduced pressure, so as to give 190 mg of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethyl methanesulfonate in the form of an orangey-coloured oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][CH2:23][CH2:22][O:21][CH3:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: COCCN
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COCCNc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-methoxyethylamine were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.81 (bs, 1H), 7.33 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 Hz and 9 Hz), 6.81 (d, 1H, J=9 Hz), 6.53 (s, 1H), 4.25 (bs, 2H), 3.54 (bs, 2H), 3.36 (s, 3H); LCMS: ret. time: 18.01 min.; purity: 100%; MS (m/e): 321 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:38][CH2:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:46])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:19])([F:18])[F:20])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-ethoxy-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M263) (0.48 g, 0.73 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (270 mg, 81%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[F:17]>CC(O)=O.C1(C)C=CC=CC=1>[Br:9][C:10]1[C:11]([F:17])=[CH:12][C:13]([NH2:14])=[C:15]([I:1])[CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Br)c(F)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Nc1cc(F)c(Br)cc1I
Temperature: 25 °C
Yield: 87 %

Procedure:
N-iodosuccinimide (2.90 ml, 28.9 mmol) was added to a solution of 4-bromo-3-fluoroaniline (5.00 g, 26.3 mmol) in AcOH (52.6 ml). The reaction was maintained at ambient temperature for 1.5 h, then diluted with 20 mL toluene and concentrated. The residue was dissolved in EtOAc and washed with 2 N aqueous NaOH. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Ultra SNAP column, 25-g silica gel loading column, 2-10% EtOAc/Heptane) to give 4-bromo-5-fluoro-2-iodoaniline (7.23 g, 22.89 mmol, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.74-7.78 (m, 1H), 6.53-6.57 (m, 1H). m/z (ESI) 315.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[C:8](/[OH:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:16]1([C:22](OCC)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CC[O-].[Na+].Cl>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:16]1([CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:22](=[O:23])[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]2[OH:15]
Reactant: CCOC(=O)/C=C(\O)c1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(=O)C2(CCOCC2)c2c(Cl)cccc2C1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of (Z)-ethyl 4-(2-chloro-6-(3-ethoxy-1-hydroxy-3-oxoprop-1-enyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (0.38 g, 0.99 mmol) in 5 mL EtOH was treated with NaOEt (freshly made from 0.1 g Na and 5 mL EtOH), and stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and diluted with 100 mL EtOAc, neutralized with 5N HCl to pH 5, washed with water (20 mL), saturated NaCl (20 mL), dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (10-40% EtOAc/hexane) to give 0.27 g yellow solid. MS m/e: (M+H)+ 337.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:5][C:6]2[NH:7][CH2:8][CH:9]([CH:15]([OH:19])[CH:16]([OH:18])[CH3:17])[NH:10][C:11]=2[C:12](=[O:14])[N:13]=1.C(O[C:24](=[O:26])[CH3:25])(=O)C>C(O)(=O)C>[C:12]([O:18][CH:16]([CH3:17])[CH:15]([O:19][C:24](=[O:26])[CH3:25])[CH:9]1[CH2:8][NH:7][C:6]2[N:5]=[C:4]([NH2:3])[NH:13][C:12](=[O:14])[C:11]=2[N:10]1[C:16](=[O:18])[CH3:15])(=[O:14])[CH3:11]
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)OC(C)C(OC(C)=O)C1CNc2nc(N)[nH]c(=O)c2N1C(C)=O
Yield: 163.3 %

Procedure:
2-Amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (0.1 g, 0.32 mmol) was slurried in acetic acid (3 ml). Acetic anhydride (300 uL, 3.2 mmol) was added and the mixture heated to reflux for 12 h. The reaction was concentrated and the crude material was purified by preparative RP-HPLC to give the final product as a white solid (0.096 g, 82%). 1H NMR (CD3OD) δ 5.15 (dd, J=2.4 Hz, J=10 Hz, 1H), 4.95-4.90 (m, 1H), 3.36 (d, J=13.6 Hz, 1H), 3.22 (dd, J=4.4 Hz, J=13.2 Hz, 1H), 2.16 (s, 3H), 2.09 (s, 3H), 1.85 (s, 3H), 1.26 (d, J=6.4 Hz, 3H). MS: ESI (positive): 368 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cccn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M55) (438 mg, 0.82 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (238 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C:25]2[N:36]([CH3:39])[N:37]=[CH:38][C:24]1=2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:26][C:25]2[N:36]([CH3:39])[N:37]=[CH:38][C:24]1=2)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added tert-butyl 4-(aminooxy)-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 137 (0.360 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 138 (0.42 g, 89%) as a white foam.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[OH:20]O>C(O)(=O)C.[Pd].C(O)C>[C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-:20])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OO
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Twenty grams of adenosine (commercialized by Sigma-Aldrich Corporation, St. Louis, Mo. USA, Product code: A9251-25G) was dispersed in one liter of acetic acid, admixed with 100 mL of hydrogen peroxide solution, and stirred at ambient temperature for five days. To the resulting solution was added five grams of 5% palladium on carbon, commercialized by Kawaken Fine Chemicals Co., Ltd, Tokyo, Japan, followed by decomposing an excessive amount of hydrogen peroxide, filtering the resultant to remove palladium carbon, drying the resulting solution in vacuo, adding ethanol to unstiffen the formed crystals, and filtering the resultant to obtain a crude crystalline adenosine N1-oxide. The crude crystals were dissolved by heating in two liters of ethanol, filtered, and ice chilled for crystallization, followed by repeating the recrystallization step twice to obtain eight grams of adenosine N1-oxide with a purity of 99.5%.
Reaction SMILES: Br[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:32])=[O:28]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)CC1(Br)OC2=CC=CC2=CC1c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1=CCCCC1
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-3-phenyl-4-benzofuranacetic acid (12.1 g., 0.0365 mole) and cyclohexene (3.3 g., 0.04 mole) in 100 ml. of chloroform is treated with 5 g. of dinitrogen tetroxide in 20 ml. of chloroform dropwise. The mixture is stirred for 16 hours at about 25° C. then at 50°-55° C. for about 20 minutes. The mixture is washed with water, and the organic layer is treated with an aqueous base. The aqueous layer is acidified, then extracted with dichloromethane. The organic layer is washed thrice with water, dried and evaporated. Two recrystallizations from benzene give light yellow solid 2-nitro-3-phenyl-4-benzofuranacetic acid, m.p. 187.5°-189.5° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][C:28](O)=[O:29])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][N:33]([CH3:32])[C:28](=[O:29])[CH2:27][O:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:24]=1
Reactant: CNOC
Reactant: O=C(O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.03 mmol of (1-trityl-1H-imidazol-4-ylmethoxy)acetic acid and 4.44 mmol of N,O-dimethylhydroxylamine hydrochloride in 100 ml of dichloromethane is mixed with 20.2 mmol of triethylamine and 4.44 mmol of propanephosphonic acid cyclic anhydride [68957-94-8] (50% in ethyl acetate). The reaction mixture is stirred at room temperature for 3 hours and diluted with dichloromethane. The phases are separated and the organic phase is washed with 1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is obtained as a pale yellowish solid from the residue by flash chromatography (SiO2 60 F). Rf=0.45 (dichloromethane-methanol 95:5); Rt=4.11 (gradient I).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[C:7](=[O:11])([O:9][CH3:10])[NH2:8].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:10][O:9][C:7]([NH:8][C:2](=[CH2:4])[C:1]([OH:6])=[O:5])=[O:11]
Reactant: CC(=O)C(=O)O
Reactant: COC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=C(NC(=O)OC)C(=O)O
Reaction time: 2 h

Procedure:
A solution pyruvic acid (4.40 g, 50.0 mmol), methyl carbamate (3.75 g, 50.0 mmol), hydroquinone (used for a polymerization inhibitor, 0.05 g), and p-toluene sulfonic acid (50 mg) in 30 ml benzene is refluxed in a 100 ml round bottom flask to which is attached a Dean-Stark trap. The system is exposed to air during the reaction. After 2 hours, 25 minutes, 0.60 ml water (33 mmol) accumulates in the trap. The yellow solution is hazy while warm, but a small amount of gelatinous precipitate accumulated upon cooling. The suspension is filtered and is evaporated. Proton nuclear magnetic resonance spectrosopy confirms the presence of the title compound; (CDCl3, ppm) 10.0-10.5 (1H, broad singlet), 5.4 (1H, broad singlet), 5.1 (1H, broad singlet), 4.5-5.0 (1H, broad singlet), 3.9 (3H, singlet).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][CH:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:32]=1)[C:39]([O:41][CH3:42])=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: COC(=O)Cc1ccccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(C)cc1C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
To a suspension of 1.05 g (9.15 mmol) of a 35% oil dispersion of KH in 15 mL of DMF was added 1.50 g (9.15 mmol) of 2-tert-butyl-4-methylphenol and the mixture was stirred under N2 at room temperature. After 10 minutes, 2.41g (91.5 mmol) of 18-crown-6 and then a solution of 2.30 g (10.1 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF were added. The reaction mixture was stirred 17 hours, then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.750 g (26%) of the title compound.