Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.C[N:11]([CH:13]=O)[CH3:12].[C:15]([O-:18])([O-])=O.[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[F:9][C:4]1[N:3]=[C:2]2[O:18][C:15]([C:6]3[CH:7]=[CH:2][C:13]([NH:11][CH3:12])=[CH:4][CH:5]=3)=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(F)nc1F
Reactant: CN(C)C=O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNc1ccc(-c2nc3ccc(F)nc3o2)cc1
Temperature: 150 °C
Yield: 89 %

Procedure:
To a solution of 4-(text-butoxycarbonyl-methyl-amino)-benzoic acid (70 mg, 0.28 mmol) in CH2Cl2 (2 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (98 μL, 0.74 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (2 mL) before 2,6-difluoro-pyridin-3-ylamine (30 mg, 0.23 mmol) was added in one portion. After an additional 30 minutes the reaction mixture was concentrated to dryness affording a residue to which was added DMF (2 mL) and K2CO3 (64 mg, 0.46 mmol). The resulting mixture was heated by microwave to 150° C. for 10 min, after which the resulting mixture was filtered, concentrated and purified by silica gel flash chromatography (0 to 100% EtOAc in hexanes) to afford [4-(5-fluoro-oxazolo[5,4-b]pyridine-2-yl)-phenyl]-methyl-amine (50 mg, 0.21 mmol, 89%). ES MS (M+H+)=244; 1H NMR (300 MHz, DMSO-d6): δ 8.24 (t, J=7.7 Hz, 1H); 7.89 (d, J=8.4 Hz, 2H); 7.18 (d, J=8.4 Hz, 1H); 6.68 (d, J=8.5 Hz, 3H); 2.76 (s, 3H); HRMS m/z 244.0883 (C13H10FN3O+H+ requires 244.0881).
Reaction SMILES: [Si](O[CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1)(C(C)(C)C)(C)C.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1
Reactant: C[Si](C)(C)Br
Reactant: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Solvent: ClCCl
Product: Fc1ccc([C@@H]2CCC(Br)O2)cc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
(5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, 1 g, 3.4 mmol) was dissolved in 10 mL of dry methylene chloride (degassed by bubbling argon prior to use). This solution was cooled to -70° C. and, while stirring at the same temperature under dry argon, trimethylsilyl bromide (550 μL, 4.1 mmol) was added dropwise. The stirring was continued for an additional 1.5 hours to yield (5S)-2-bromo-5-(4-fluorophenyl) tetrahydrofuran which was used without isolation (see below). In a separate flask, 3-t-butyldimethylsilyloxy-but-1-yne (840 mg, 4.5 mmol) was dissolved in dry THF (10 mL). The solution was cooled to -60° C. and, while stirring at the same temperature under dry argon, n-butyllithium (1.8 mL of 2.5M solution in hexane, 4.5 mmol) was added dropwise. The stirring was continued for an additional 0.5 hours. The resulting solution was added dropwise, through a cannula to the stirred solution of the 2-bromotetrahydrofuran (made above) at -70° C. The stirring was continued at -78° C. for additional 1.5 hours. The reaction flask was then left in the freezer (-78° C.) over night (though the TLC did not show any change). The reaction mixture was poured into 2M solution of ammonium chloride (100 mL) and extracted with methylene chloride (3×75 mL). The solution was dried over sodium sulfate and the solvent removed in vacuo; The residue was purified via flash column chromatography (eluent, 10% ethyl acetate in hexane) to obtain two components. From the proton NMR analysis, the less polar one was identified as (2S,5S)-trans-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (213, 765 mg, 65%). 1H-NMR (CDCl3) δ 7.29 (2H, m), 7.01 (2H, t, J=8.7 Hz), 5.09 (1H, t, J=7.1 Hz), 4.91-4.97 (2H, m), 4.55-4.62 (1H, m), 2.26-2.50 (2H, m), 2.05-2.17 (1H, m), 1.75-1.88 (1H, m), 1.38 (3H, d, J=6.6 Hz), 0.90 (9H,s), 0.12 (6H, s). The more polar component was assigned to be (2R,5S)-cis-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (214, 190 mg, 16%).
Reaction SMILES: O1C2C=CC(C3(CC(OC)=O)C4C(=CC=CC=4)N(CCCCC)C3=O)=CC=2OC1.[O:30]1[C:34]2[CH:35]=[CH:36][C:37]([C:39]3([CH2:54][CH2:55][C:56]([O:58]C)=[O:57])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:40]3=[O:53])=[CH:38][C:33]=2[O:32][CH2:31]1>>[O:30]1[C:34]2[CH:35]=[CH:36][C:37]([C:39]3([CH2:54][CH2:55][C:56]([OH:58])=[O:57])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:40]3=[O:53])=[CH:38][C:33]=2[O:32][CH2:31]1
Reactant: CCCCCN1C(=O)C(CCC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Agent: CCCCCN1C(=O)C(CC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C(CCC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 11E, and making non-critical variations to replace methyl [3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetate with methyl 3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoate, the title compound was obtained (92%) as a colorless solid: MS (ES−) m/z 394.2 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C1COCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:43]3[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Yield: 79.4 %

Procedure:
A mixture of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (0.333 g, 0.65 mmol), 1-(methylsulfonyl)piperazine (0.32 g, 2 mmol), and DIPEA (0.17 g, 1.3 mmol) in THF (50 mL) was heated under reflux for 3 hrs. The solution was concentrated and then diluted with 100 mL of water containing 1% HOAc to give a solid, which was collected and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (4:1), followed by recrystallization from MeOH, gave 0.33 g (79% yield) of tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate: mp 223° C. (decomp.); 1H NMR (CDCl3) δ 8.63 (br s, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 6.62 (br s, exchangeable with D2O, 1H), 6.35 (d, J=1.7 Hz, 1H), 4.09-3.80 (m, 15H), 3.35 (m, 4H), 2.80 (s, 3H), 1.52 (s, 9H); Anal. Calcd. for C26H35F2N9O6S: C, 48.8; H, 5.5; N, 19.7. Found: C, 48.9; H, 5.6; N, 19.9%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([CH3:23])=[C:4]([CH:3]=1)[C:24]([NH:25][CH2:26][C:27]1[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
A stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1.3 g, 2.39 mmol) in DCM (10 mL) was cooled to 0° C. and TFA (2 mL) was added to it. Reaction mass was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. Combined organic layers were dried over sodium sulfate and concentrated to afford the desired compound (0.9 g, 85%). LCMS: 461.15 (M+1)+; HPLC: 98.52% (@ 254 nm) (Rt; 4.673; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (t, 1H), 7.19 (s, 1H), 7.01 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H, J=4 Hz), 2.91 (d, 2H, J=11.6 Hz), 2.78 (bs, 1H), 2.55 (s, 3H), 2.32-2.35 (m, 2H), 2.18 (s, 3H), 2.10 (s, 6H), 1.44-1.50 (m, 4H).
Reaction SMILES: [Si]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:48])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([O:37][CH2:38][CH2:39][NH:40]C(=O)OC(C)(C)C)=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:24][CH2:23]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C>Cl.C(O)(C)C>[NH2:40][CH2:39][CH2:38][O:37][C:35]1[CH:34]=[CH:33][C:32]2[C:28]([CH:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][C:17]4[C:18](=[O:19])[N:13]5[CH2:12][CH2:11][CH2:10][CH:9]([OH:8])[C:14]5=[N:15][C:16]=4[CH3:48])[CH2:27][CH2:26]3)=[N:29][O:30][C:31]=2[CH:36]=1.[OH:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:48])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:24][CH2:23]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(OCCNC(=O)OC(C)(C)C)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(OCCN)ccc34)CC1)CCCC2O
Temperature: 60 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
A solution of tert-butyl (2-((3-(1-(2-(9-((tert-butyldimethylsilyl)oxy)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl)piperidin-4-yl)benzo[d]isoxazol-6-yl)oxy)ethyl)carbamate, prepared as described in the previous step, (70 mg, 0.103 mmol) in HCl/isopropanol (10 mL, 5 N) was stirred for 1 h at 60° C. The reaction mixture was evaporated at 40° C. under reduced pressure and dissolved carefully in aqueous saturated sodium bicarbonate solution (5 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure at 40° C. The aqueous layer still contained product, which was recovered by evaporating the aqueous layer to dryness at 40° C. under reduced pressure. The resulting residue from the aqueous layer was re-dissolved in water and brought over a conditioned Waters Oasis SPE (6 cc) column and afterwards eluted with methanol. The methanol elution fraction was combined with the residue of the dichloromethane extraction and evaporated to dryness at 40° C. under reduced pressure to yield the title compound along with a side product (ESI-MS (M+1) 468; side product being 5% 9-hydroxy-3-(2-(4-(6-hydroxybenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (M+1) 425). The mixture was used in the next step without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[CH:16]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]3)[C:7]=2[CH:16]=1
Reactant: COc1ccc2nnc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2nnc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 34 %

Procedure:
A mixture of [6-(methyloxy)-3-oxo-1,2,4-benzotriazin-4(3H)-yl]acetaldehyde (as the methyl hemiacetal) (89 mg, 0.346 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (69 mg, 0.346 mmol) in chloroform (5 ml) and MeOH (0.5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (220 mg, 1.038 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (20 ml). The reaction was then extracted with 20% MeOH in DCM (3×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-5% MeOH/DCM gradient to provide the desired compound (48 mg, 34%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([NH+:7]([O-:36])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccncc1)c1ccc(OCC2CC2)c2oc3ccccc3c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCC2CC2)c2oc3ccccc3c12)[NH+]([O-])c1ccncc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
A suspension of N-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg, 0.139 mmol) (example 28) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.698 mmol) in chloroform (10 ml) was stirred at room temperature for 12-16 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 40% acetone-chloroform as the eluent to give 25 mg of N-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 266-268° C.
Reaction SMILES: Br.[NH2:2][C@@H:3]([CH2:7][CH2:8][Br:9])[C:4]([OH:6])=[O:5].S(Cl)([Cl:12])=O.[CH2:14](O)[CH3:15]>>[ClH:12].[CH2:14]([O:5][C:4](=[O:6])[C@@H:3]([NH2:2])[CH2:7][CH2:8][Br:9])[CH3:15]
Reactant: N[C@@H](CCBr)C(=O)O
Reactant: CCO
Reactant: O=S(Cl)Cl
Agent: Br
Product: CCOC(=O)[C@@H](N)CCBr
Product: Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-amino-4-bromo-butyric acid hydrobromide (2 g, 7.6 mmol) in ethanol (10 ml), at 0° C., was added thionyl chloride (1.11 ml, 15.21 mmol). The solution was stirred at 70° C. for 1 hour, cooled and concentrated in vacuo. Heptane added and mixture concentrated under high vac. Ether was added and the precipitate stirred for 1 hr, filter and dried in vacuo to provide (S)-2-amino-4-bromo-butyric acid ethyl ester hydrochloride as an sticky white solid (1.9 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[CH2:23][NH:24][C:25]([NH2:27])=S.[CH3:28]I.C[N:31]([CH3:34])C=O>>[N:31]1[CH2:34][CH2:28][NH:27][C:25]=1[NH:24][CH2:23][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]=1[CH3:1]
Reactant: CI
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CNC(N)=S
Reactant: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CNC1=NCCN1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-thioureidomethylpyrimidine (0.7 g) and methyl iodide (0.31 g) in N,N-dimethylformamide (20 ml) was stirred for 7 hours at a room temperature. After evaporating the solvent in vacuo, the residual product was dissolved in ethanol (14 ml). Ethylenediamine (0.33 g) was added thereto and refluxed for 2 hours. After cooling, the reaction mixture was poured into a mixture of chloroform (50 ml) and water (100 ml), and adjusted pH to 11.0 with 10% aqueous potassium carbonate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, evaporated in vacuo. The residual product was subjected to column chromatography on alumina eluting with a mixture of chloroform and methanol (50:1). The fractions containing the object compound were combined and concentrated in vacuo. The residue was recrystallized from ethanol to give 5-(1-imidazolin-2-ylaminomethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (0.06 g).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O-].[Na+].Cl[C:13]1[C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH3:19])[N:16](C)[N:17]=1>CN(C=O)C>[CH2:1]([S:8][C:13]1[N:17]([CH3:9])[N:16]=[C:15]([CH3:19])[C:14]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1c([N+](=O)[O-])c(Cl)nn1C
Reactant: SCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(SCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
Benzylmercaptan (50.8 g) (0.41 mol) was added to 21 g of sodium methoxide in 480 ml of DMF under ice-cooling and then 65.2 g (0.37 ml) of 5-chloro-2,3-dimethyl-4-nitropyrazole was added. After stirring at room temperature for 3 hr., DMF was evaporated under reduced pressure, and the residue was diluted with ice-water. The precipitated solids were filtered, washed with water and further with n-hexane and dried to give 82.4 g of the title compound. m.p. 82 -83° C.
Reaction SMILES: N1C=CC=CC=1.Cl[S:8]([OH:11])(=[O:10])=[O:9].[CH3:12][N:13]([CH3:16])[CH:14]=[O:15]>>[CH3:12][N:13]([CH3:16])[CH:14]=[O:15].[S:8](=[O:11])(=[O:10])=[O:9]
Reactant: O=S(=O)(O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=S(=O)=O

Procedure:
On the contrary, when a tertiary amine such as pyridine is mixed with dimethyl formamide and then chlorosulfonic acid is added to the mixture, dimethyl formamide-sulfur trioxide is formed as well as the case adding the tertiary amine to a mixture of dimethyl formamide and chlorosulfonic acid. When the mixture is used for the reaction of L-ascorbic acid in which the 5- and 6-positions are protected by a ketone or aldehyde the yield of the product is remarkably high and the product in the reaction mixture is crystallized in high degree.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:2].[BH4-].[Na+].O>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(CO)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
1.8 g of t-butyl N-(5-formyl-2-methoxybenzyl)carbamate was dissolved in 12 ml of ethanol and 6 ml of tetrahydrofuran, and 0.15 g of sodium borohydride was added. After stirring at room temperature overnight, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography, to give 1.65 g of the title compound from the 1:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][C:27]=1[CH3:34]>C(OCC)(=O)C.CCCCCC>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])=[CH:28][C:27]=1[CH3:34]
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: Cc1cc(CN)ccc1F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCN3C(C)C)ccc1F
Yield: 93.7 %

Procedure:
Coupling of 6-(benzyloxy) 1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluoro-3-methylbenzylamine (0.133 g, 0.95 mmol) as described for the synthesis of intermediate 3 gave 0.384 g (93% yield) of the title amide as white crystals (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.6 Hz, 2×CH3), 2.25 (3H, broad d, J=1.8 Hz, CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.41 (1H, m, CH), 4.46 (2H, d, J=5.8 Hz, NCH2), 5.08 (2H, s, OCH2), 6.94 (1H, m, aromatic), 7.04-7.08 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.3-7.36 (3H, m, aromatics), 7.42-7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). HRMS (ESI+) calculated for C25H28FN4O3 [M+H+]: 451.2145. found: 451.2141.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[C:5]2C(=O)[O:9][C:7](=[O:8])[C:6]2=[CH:12][C:13]=1[F:14]>C(COC)OC>[F:2][C:3]1[CH:4]=[C:5]([NH2:1])[C:6](=[CH:12][C:13]=1[F:14])[C:7]([OH:9])=[O:8]
Reactant: N
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Solvent: COCCOC
Product: Nc1cc(F)c(F)cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Dimethoxyethane (43 parts) was charged to a reactor and ammonia was bubbled in to form a saturated solution. The ammonia addition was maintained while a solution of 1.84 parts of 4,5-difluorophthalic anhydride in 13 parts of dimethoxyethane was added slowly over a period of 0.5 hours. The reaction mixture was stirred for an additional 5 minute period and the dimethoxyethane was removed by vacuum distillation. The remaining white solid (the ammonium salt of 4,5-difluorophthalamic acid) was dissolved in 20 parts of aqueous sodium hydroxide (40% NaOH) and the solution was de-gassed under moderately reduced pressure to remove any remaining ammonia; then heated at atmospheric pressure, to 50° C. and maintained at that temperature while 14.1 parts of a 5.78% aqueous sodium hypochlorite solution was added. The solution was then heated to 60°-65° C. and maintained at that temperature, with stirring for about 30 minutes; then cooled to about 20°-25° C. and acidified to a pH of 4-6, by addition of concentrated hydrochloric acid. A precipitate formed and the mixture was extracted with chloroform. The acidification procedure was repeated until no additional precipitate formed. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the chloroform removed by vacuum distillation to yield 1.34 parts of solid 4,5-difluoroanthranilic acid having a melting point of 180°-181° C. The chemical structure of the product was confirmed by infrared analysis.
Reaction SMILES: [O:1]=[C:2]([C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31]([O:1]/[C:2](/[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])=[C:3](\[C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:11]=1)/[C:4]#[N:5])=[O:36]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(/C(OC(=O)C(C)(C)C)=C(\C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 7 °C
Reaction time: 20 h
Yield: 73.3 %

Procedure:
In a 10 L-reaction flask, 594 g (1.92 mol) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile and 6000 g of tetrahydrofuran were added, 214 g (2.11 mol) of triethyl amine was added and then 255 g (2.11 mol) of pivaloyl chloride was added dropwise at 25 to 27° C. over 1 hour. After reacting for 20 hours, tetrahydrofuran was removed by concentrating under a reduced pressure, and then 1800 g of toluene and 1800 g of water were added to separate out toluene phase. After distilling out toluene, 794 g of hexane was added and dissolved, and crystallization was carried out by gradually cooling to 7° C. After filtering, the crystal was washed with 1000 g of hexane cooled at 5° C., dried to obtain 554 g (yield 73.4%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) acrylonitrile.