Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].Cl.Cl[CH2:17][C:18]1[S:22][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:20][CH:19]=1.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH:8]1([NH:7][C:5](=[O:6])[C:4]2[CH:11]=[CH:12][C:13]([F:14])=[C:2]([O:1][CH2:17][C:18]3[S:22][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:20][CH:19]=3)[CH:3]=2)[CH2:9][CH2:10]1
Reactant: ClCc1cnc(Nc2ccccn2)s1
Reactant: O=C(NC1CC1)c1ccc(F)c(O)c1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(F)c(OCc2cnc(Nc3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
To a suspension of NaR (16 mg, 60% in oil) in DMF (1 mL) was added a solution of 3-hydroxy-4-fluoro-N-cyclopropylbenzamide (58.5 mg, 0.3 mmol) in DMF (1 mL) at RT. After 10 min, (5-chloromethylthiazol-2-yl)pyridin-2-ylamine hydrochloride (Example 10A) (52.4 mg, 0.2 mmol) was added. The mixture was stirred at RT for 1 h and poured onto ice. The mixture was neutralized with 1 N KHSO4 solution and the precipitates were collected, washed with water and ethyl acetate to give the title compound as a light yellow solid (25.2 mg, 33%). MS m/z 385 (M+H)+.
Reaction SMILES: C1C=CC(C2C=CC([C:13]3[NH:34][C:32](=O)[C:15]4=[C:16](C5C=CC(C6C=CC=CC=6)=CC=5)[NH:17][C:18](=[O:19])[C:14]=34)=CC=2)=CC=1.N(CCO)(CCO)CC[OH:38]>O>[O:38]=[C:14]1[C:13]2[C:16]([CH:15]=[CH:32][N:34]=2)=[N:17][C:18]1=[O:19]
Reactant: O=C1NC(c2ccc(-c3ccccc3)cc2)=C2C(=O)NC(c3ccc(-c4ccccc4)cc3)=C12
Reactant: OCCN(CCO)CCO
Solvent: O
Product: O=c1nc2ccnc-2c1=O
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 264 (in which the content of metal ions having a valence of at least 2 was 520 ppm), 60 g of the same aqueous dispersion of the pigment derivative (n) as that obtained in Example 45 and 60 g of deionized water were mixed, 11 g of 2% by weight triethanolamine was added so as to adjust the neutralization ratio of the pigment derivative to 100%, and the mixture was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a pigment dispersion.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(N)nc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Yield: 18.1 %

Procedure:
To a solution of 2,5-diaminopyridine (1.00 g, 9.16 mmol) and pyridine (0.889 ml, 11.0 mmol) in tetrahydrofuran (30 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.52 ml, 11.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 471 mg (18.1%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:9][C:8](=[O:19])[NH:7][C:6]=1[CH2:20][O:21][CH3:22])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:34]([O:36][C:37]2[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=2)=[O:35])[C:8](=[O:19])[NH:7][C:6]=1[CH2:20][O:21][CH3:22])=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reaction time: 0.17 h

Procedure:
To a solution of (+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorophenyl)-pyrimidine (1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at −78° C. under argon atmosphere, a solution of lithium hexamethyldisilazide in THF (1M, 18.0 mL, 18.0 mmol) was added over 2-3 min. and the mixture was stirred for 10 min. This solution was added over 6 min., via a cannula, to a stirred solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at −78° C. Stirring was continued for 10 min. and the mixture was poured onto ice (50 g) and extracted with chloroform (2×50 mL). The combined extracts were dried (sodium sulfate) and the solvent was evaporated. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 4/1 to 3.5/1) as the eluent. The product was obtained as yellow syrup which upon trituration with hexanes became a white powder (2.40 g, 79%): 1H NMR d 3.52 (s, 3H), 3.74 (s, 3H), 4.65-4.80 (q, J=16.5 Hz, 2H), 6.32 (s, 1H), 7.10-7.30 (m, 4H), 7.36 (d, J=9 Hz, 2H), 8.27 (d, J=9 Hz, 2H).
Reaction SMILES: O[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.S(Cl)([Cl:19])=O>ClCCl>[ClH:19].[Cl:19][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: OC(CCc1ccccc1)Cn1ccnc1
Solvent: ClCCl
Product: Cl
Product: ClC(CCc1ccccc1)Cn1ccnc1

Procedure:
A solution of 1.00 g. of 1-(2-hydroxy-4-phenylbutyl) imidazole in 40 ml. of dichloromethane was treated with 1 ml. of thionyl chloride with stirring and the solution heated to gentle reflux for one hour. Evaporation to dryness afforded 1-(2-chloro-4-phenylbutyl) imidazole hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC([N:31]1[CH2:35][CH2:34][C@H:33]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:32]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([C@H:33]4[CH2:34][CH2:35][NH:31][CH2:32]4)[CH:40]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn([C@H]4CCNC4)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (20 mg, 0.048 mmol), (S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (26 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.10 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was stirred at 100° C. for 30 min in the microwave reactor. Then, the mixture was passed through PL-Thiol MP SPE+ resin and concentrated in vacuo. The resulting solid was left to stir in DCM (0.2 mL) and TFA (0.2 mL) at rt for 30 min. Purification via MDP afforded the title compound as a white solid. MS (ES+): m/z: 475.96/477.94 (70/50) [MH+]. HPLC: tR=2.35 min (ZQ3, polar—5 min). 1H NMR (400 MHz, CD3OD): δ 1.89 (d, J=6.6 Hz, 3H), 2.40 (ddd, J=13.9, 7.6, 3.3 Hz, 1H), 2.50-2.62 (m, 1H), 3.50 (ddd, J=11.5, 8.8, 4.4 Hz, 1H), 3.63-3.73 (m, 2H), 3.75-3.82 (m, 1H), 5.28 (q, J=6.4 Hz, 1H), 6.53 (q, J=6.8 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.39 (dd, J=8.9, 4.9 Hz, 1H), 7.79 (s, 1H), 7.89 (s, 1H), 8.14 (d, J=4.8 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:13]1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>CC(N(C)C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:13]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COC(=O)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reaction time: 2.5 h
Yield: 26.5 %

Procedure:
A mixture of 2-Chloro-5-nitropyridine (1.59 g, 10 mmol) and methyl piperidin-4-ylacetate hydrochloride (1.8 g, 10 mmol) (prepared as described in Patent Application WO 2000029407) in DMA (50 mL) was treated with 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) (15 g of a 2.2 mmol/g loading on polystyrene support, 33 mmol). The resulting mixture was stirred for 2.5 h then filtered through diatomaceous earth. Volatile material was removed by evaporation to give the title compound (740 mg, 21%) as a solid; 1H NMR δ 1.08-1.28 (2H, m), 1.77 (2H, d), 1.99-2.12 (1H, m), 2.29 (2H, d), 3.07 (2H, t), 3.60 (3H, s), 4.51 (2H, d), 6.94 (1H, d), 8.13-8.25 (1H, m), 8.95 (d, 1H); MS m/e MH+ 280.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+]=[N-])[CH:46]([O:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:45]2)[CH:7]([CH3:61])[CH2:6][CH2:5][C:4]1=[O:62])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:45]2)[CH:7]([CH3:61])[CH2:6][CH2:5][C:4]1=[O:62])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.3 %

Procedure:
17-Ethyl-1-hydroxy-12-[2'-(4"-azido-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (64 mg) in THF (1.5 mml) containing 1 drop of water was treated with triphenylphosphine (24 mg) and the mixture stirred at room temperature for 72 hours. The reaction mixture was purified directly by preparative thin layer chromatography eluting with 90% dichloromethane:10% methanol to give the title compound (43 mg, 68%) as a white solid. (1H NMR analysis was consistent with the desired structure).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]([S:13][C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=3)=[C:4]2[C:3]1=[O:26].[NH2:27][OH:28].Cl.C[O-].[Na+]>CO>[OH:28][NH:27][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([S:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]3[CH2:24][CH2:25][N:2]([CH3:1])[C:3](=[O:26])[C:4]=23)=[CH:23][CH:22]=1
Reactant: NO
Reactant: COC(=O)c1ccc(Sc2c3n(c4ccccc24)CCN(C)C3=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCn2c(c(Sc3ccc(C(=O)NO)cc3)c3ccccc32)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
To a solution of methyl 4-((2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl)thio)benzoate (0.25 g, impure) and NH2OH.HCl (0.35 g) in 4 mL of dry MeOH was added 1.4 mL of 25% NaOMe solution in methanol. The reaction mixture was stirred for 20 min at r.t. and 0.3 mL of more 25% NaOMe solution in methanol was added. After stirring for 2 h, the reaction mixture was quenched with 10 mL of potassium phosphate buffer solution. The mixture was extracted with 2×30 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluted with up to 10% MeOH/CH2Cl2 to give 0.097 g of the title product as beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]NC(=O)CCC(N)=O>CC(O)=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([Br:28])=[CH:12][N:11]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC(=O)O
Product: O=c1c(Br)cn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one (2.41 g, 6.8 mmol) in AcOH (68 mL) was added N-bromosuccinamide (2.67 g, 15 mmol) and the reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by flash chromatography (80 g SiO2, 0-100% ethyl acetate/hexanes) to provide 3-(benzyloxy)-1-(biphenyl-3-yl)-5-bromopyridin-4(1H)-one. LC/MS (M+H)+ 432/434.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH:12]=[O:13])=[N:7]2.[OH-:19].[Na+].OO.Cl>CO.OO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([C:12]([OH:19])=[O:13])=[N:7]2
Reactant: [OH-]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a slurry of 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (306a) (250 mg, 0.81 mmol) in MeOH (0.4 mL) and NaOH 1.0 N (1.62 mL, 1.62 mmol) was added two drops H2O2 30% in water (0.10 mL, 1.01 mmol) from a pasteur pipette. The reaction was stirred rapidly at RT and became a yellow/orange solution. Additional 0.05 mL 30% aq H2O2 was added. After 30 min, additional 0.05 mL 30% aq H2O2 was added. After 30 min, the reaction mixture was treated with ice, acidified to pH <2 with 1.0 N HCl, and diluted with 10 mL water. The orange suspension was filtered, rinsing with 10 mL of water to give 5-bromo-3-(tert-butylamino)quinoxaline-2-carboxylic acid (0.26 g, 0.80 mmol, 99% yield) as an orange solid. m/z (ESI, +ve ion) 324.0/326.0 (M+H)+.
Reaction SMILES: [Na].C[O-].[Na+].[F:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH:23]=1)[CH:21]=O>CO>[F:5][C:6]1[CH:14]=[CH:13][C:9](/[C:10](=[CH:21]/[C:20]2[CH:23]=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=2[N+:24]([O-:26])=[O:25])/[C:11]#[N:12])=[CH:8][CH:7]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(/C=C(\C#N)c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
Sodium metal (0.836 g, 0.0363 mol) was dissolved in MeOH (40 mL), and the resulting sodium methoxide solution was cooled to 0° C. To this was added 4-fluorobenzyl cyanide (4.9 g, 0.0363 mol), and the mixture stirred for 30 min. at 0° C. 5-Methyl-2-nitrobenzaldehyde (3.0 g, 0.0181 mol) was added at the same temperature, and the reaction mixture was stirred for a further 1 h at 0° C. After completion of reaction (monitored by TLC), the precipitated solid was isolated by filtration to give the desired compound as a light yellow colored solid (3.0 g, 58% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2F)[CH2:5][CH2:4]1.[F:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:25])([F:26])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:30]2[CH2:31][CH2:32][C@@H:28]([F:27])[CH2:29]2)[CH2:7][CH2:8]1
Reactant: F[C@@H]1CCNC1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(F)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2,3-difluoro-4-methylamino-5-nitro-benzoic acid amide (200 mg, 0.52 mmol), (R)-3-fluoropyrrolidine×HCl (72 mg, 0.57 mmol), DIPEA (0.76 mL, 4.4 mmol) and MeCN (5 mL). Yield: 230 mg. HPLC Rt=1.52 min (method A). MS m/z: 451 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccnc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccn1

Procedure:
A mixture of 4-aminopicolinic acid (2.50 g, 18.1 mmol) and conc. sulfuric acid (2 mL, 37.3 mmol) in 50 mL methanol was refluxed for 20 h. The mixture was concentrated i. vac., then 50 mL dichloromethane were added and made basic by addition of conc. ammonia (aq). Then water and NaCl (aq, sat.) were added and the aqueous layer was extracted with methylenechloride/methanol=9:1. The combined organic layers were dried over MgSO4 and then evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(CC)Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reaction time: 5 h

Procedure:
A mixture of 6.5 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole, 7.5 g of potassium carbonate, 5.16 g of ethyl 2-bromobutyrate and 100 ml 2-butanone is heated under reflux with stirring for 5 hr. The reaction mixture is poured into ice/dil hydrochloric acid. The oil, which solidified on scratching, was collected and dried in vacuo. Recrystallization from isopropyl ether (decolorizing carbon) gives ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyrate, mp 73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]=[CH:9][N:10](C)C)[S:5][CH:6]=1.O.[NH2:15]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][NH:10][N:15]=2)[S:5][CH:6]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cc(Cl)cs1
Solvent: CCO
Solvent: O
Product: Clc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 1-(4-chloro-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (24.6 mmol) and hydrazine hydrate (49.2 mmol) in 25 mL ethanol was refluxed for 15 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and dried in vacuum to afford 4.5 g (99% yield) 3-(4-chloro-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([CH3:11])[N:3]=1
Reactant: CO
Reactant: Cc1nc(N)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(N)nc1C

Procedure:
6-Amino-2-methylnicotinic acid (1.00 g) was suspended in methanol (15 mL), concentrated sulfuric acid (0.5 mL) was added, and the mixture was stirred with heating under reflux for 18 hr. The reaction mixture was cooled, aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (0.82 g).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:7]1[N:8]=[C:3]([CH:2]([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[N:6]=1
Reactant: O=c1nc(-c2ccc(C(F)(F)F)nc2)cc(C(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1

Procedure:
The title compound was prepared from 6-difluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-1H-pyrimidin-2-one (6.37 g, 0.022 mol) and phosphoroxychloride (34 ml) according to the general procedure I. Obtained as a brown oil (6.65 g, 98%). MS (ISP) 310.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.CC1C=CC2C(=CC=C(C)C=2)C=1.[CH3:25][OH:26]>>[CH3:12][C:7]1([CH:25]=[O:26])[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH2:8]1
Reactant: Cc1cccc2c(C)cccc12
Reactant: CO
Agent: Cc1ccc2cc(C)ccc2c1
Product: Cc1cccc2c1C=CCC2(C)C=O

Procedure:
The experiment was carried out in the same manner as in Example 6, except that in Example 6, 1,5-dimethylnaphthalene obtained in Production Example 2 was used in place of the 2,6-dimethylnaphthalene and that methanol was added, thereby obtaining 100 g of a 1,5-dimethylnaphthalene formaldehyde resin which is a viscous liquid at ordinary temperature. The reaction condition and physical properties of the obtained resin are shown in Table 2.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:5]2[C:4]1=[O:13].[CH2:14](Cl)[CH3:15]>>[CH2:14]([O:2][N:3]1[C:4](=[O:13])[CH:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:6]2[C:7]1=[O:8])[CH3:15]
Reactant: O=C1C2CCCCC2C(=O)N1O
Reactant: CCCl
Agent: [Na]
Product: CCON1C(=O)C2CCCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.4 %

Procedure:
In an autoclave 60 g of a 20 wt % solution of the sodium salt of N-hydroxyhexahydrophthalimide (0.063 mol) and 5.0 g (0.078 mol) of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was maintained at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction product was extracted from the mixture with toluene. Gas chromatographic analysis of the toluene extract showed that the yield was 79% of N-ethoxyhexa-hydrophthalimide (0.050 mol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)=O)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1COCC1.O.[OH-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCCC(c2ccc3c(c2)OCO3)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)OC[C@H](CN1CCCC(c3ccc4c(c3)OCO4)C1)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 83.8 %

Procedure:
(3-Benzo[1,3]dioxol-5-ylpiperidin-1-yl-(R)-2,3-dihydrobenzo[1,4]dioxin-2-ylmethanone (285 mg, 0.77 mmol) was dissolved in dry DMF (2.5 ml) and 1 M BH3 THF (3.10 ml, 3.10 mmol) was slowly added under a nitrogen atmosphere. The reaction mixture was stirred for 4.5 h at RT and then cooled to 0° C. Water was slowly added and the mixture basified with 2.5 M NaOH and extracted three times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The crude product was dissolved in methanol (25 ml) and 5 M HCl (1.5 ml) was slowly added. The mixture was stirred for 1 h at RT and then at 60° C. for 2 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc and washed twice with 1 M Na2CO3 and water. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness to give 228 mg of the title compound.