Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH3:17][CH2:18][O-:19].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([O:19][CH2:18][CH3:17])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CC[O-]
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and sodium ethylate in ethanol. Anal. found C 57.39%, H 4.38%, N 24.34%. C 11H10N4O2 requires C 57.43%, H 4.47%, N 24.42%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:11]2[CH2:14][CH:13]([NH:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH2:12]2)=[CH:6][CH:5]=1.Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH:13]([N:15]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:33](=[O:34])[O:35][CH3:36])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(=O)Cl
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.4 mg of a 75% dispersion of sodium hydride in mineral oil are added, at room temperature under an argon atmosphere, to a solution of 330 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorobenzyl)amine in 25 cm3 of tetrahydrofuran. The mixture is stirred at room temperature for 1 hour before adding thereto 59 mm3 of methyl chloroformate, and then the stirring is maintained for 18 hours under the same conditions. The reaction mixture is supplemented with 0.3 cm3 of distilled water and the tetrahydrofuran is expelled in a rotary evaporator. The residue obtained is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (97.5/2.5 by volume)]. 328 mg of methyl {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorobenzyl)carbamate are obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.97 (mt: 2H); 3.39 (mt: 2H); 3.71 (s: 3H); 4.24 (broad s: 1H); 4.45 (unresolved complex: 1H); 4.57 (s: 2H); from 6.65 to 6.80 (mt: 3H); from 7.15 to 7.30 (mt: 8H)].
Reaction SMILES: N1CCCCC1.[CH:7]1([CH2:13][C@H:14]([NH:22][C:23](=[O:43])[C@@H:24]([NH:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:34])[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[C@@H:15]([OH:21])[C@H:16]([CH:18]2[CH2:20][CH2:19]2)[OH:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N:44]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][CH2:49][C@@H:45]1[C:46](O)=[O:47]>C(Cl)Cl>[C:55]([O:54][C:52]([N:44]1[CH2:51][CH2:50][CH2:49][C@@H:45]1[C:46](=[O:47])[NH:34][C@H:33]([C:32](=[O:42])[NH:31][C@H:24]([C:23](=[O:43])[NH:22][C@@H:14]([CH2:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C@@H:15]([OH:21])[C@H:16]([CH:18]1[CH2:19][CH2:20]1)[OH:17])[CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 19, by condensing (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide with Fmoc-Phe-OH there was obtained 9H-fluoren-9-ylmethyl [(S)-α-[[(S)-1-[[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate which, by reaction with piperidine in methylene chloride, was converted into (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-α-[(3-phenyl-L-alanyl)amino]imidazole-4-propionamide. Further condensation with Boc-D-Pro-OH, analogously to Example 19, yielded (R)-2-[[(S)-α-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylic acid tert-butyl ester as an amorphous solid, MS: 709 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][Cl:21])=[CH:7][CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: COc1c(CO)cccc1Sc1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1c(CCl)cccc1Sc1ccccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-methoxy-3-(2-chlorophenylthio)benzyl alcohol (9 g), thionyl chloride (4.6 ml) and pyridine (3 drops) in dried benzene (60 ml) was refluxed under heating for 30 minutes. The reaction mixture was cooled to the ambient temperature and evaporated under reduced pressure. The residue was dissolved in diethyl ether, and the solution was washed with water, saturated aqueous sodium bicarbonate and water in turn, dried over magnesium sulfate and then evaporated under reduced pressure to give oily 2-chlorophenyl 2-methoxy-3-chloromethylphenyl thioether (9.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br>>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)c1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: COC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 76 %

Procedure:
Methyl 2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (Example 100) (16.15 g, 56.0 mmol) and 2,6-difluorobenzyl bromide (14.67 g, 70.86 mmol, 125 M%) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding white crystals of methyl 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (17.63 g, 42.55 mmol, 76% yield). M.p. 184-186° C. 1H NMR (200 MHz, CD2Cl2): δ7.94 (dd, J=1.1, 7.6 Hz, 1H, H5), 7.72 (dd, J=1.1, 8.2 Hz, 1H, H7), 7.56 (m, 1H, H4′), 7.37 (dd, J=7.6, 8.2 Hz, 1H, H6), 7.26 (m, 1H, H4″), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.39 (s, 2H, CH2PhF2), 3.95 (s, 3H, CO2CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([NH:7][C:8](=[O:34])[C@@H:9]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([OH:25])[CH:12]=1)([CH3:6])[CH3:5].[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:35])[C:4]([NH:7][C:8](=[O:34])[C@@H:9]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([O:25][C:39](=[O:40])[NH:38][CH2:36][CH3:37])[CH:12]=1)([CH3:6])[CH3:5]
Reactant: CCN=C=O
Reactant: COC(=O)C(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)Oc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
2-[(S)-3-(4-benzyloxy-3-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionylamino]-2-methyl-propionic acid methyl ester (1.2 mmol), was dissolved in dichloromethane (5 ml) and ethyl isocyanate (0.31 ml) added. A catalytic amount of DMAP was added and the solution was heated at 50° C. for 7 hours. The reaction mixture was evaporated to dryness and the crude product purified by chromatography on silica gel eluting with a mixture of ethyl acetate-hexane. 2-[(S)-3-(4-Benzyloxy-3-ethylcarbamoyloxy-phenyl)-2-tert-butoxycarbonylaminopropionyl-amino]-2-methyl-propionic acid methyl ester was obtained as a white crystalline solid, 410 mg; Rf 0.29 (ethyl acetate-hexane 1:1); NMR (500 MHz, CDCl3) 1.39 (ca 3H, s), 1.41 (ca 3H, s), 1.43 (ca 9H, s), 2.86 (1H, dd J 14, 8), 3.08 (1H, dd J 14, 5), 3.25-3.32 (2H, m), 3.70 (3H, s), 4.23 (1H, br), 5.00 (1H, br t J 5), 5.07 (2H, s), 6.15 (1H, s), 6.91 (1H, d J 8), 6.99-7.02 (2H, m), 7.28-7.42 (ca 5H, m); HPLC/MS retention time 5.98 min, m/z 558 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: Fc1ccccc1Cc1n[nH]c2ncccc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3cccnc32)n1

Procedure:
A solution of 150 mg (0.66 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine from example 12A, 96 mg (0.66 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 12 mg (0.013 mmol) of tris(di-benzylideneacetone)dipalladium, 19 mg (0.040 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 300 mg (0.92 mmol) of cesium carbonate in 4 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with water and a little methanol and extracted with ethyl acetate. The organic phase is concentrated in vacuo, and the residue is stirred with methanol and filtered off with suction. 62 mg (28% of theory) of the desired compound are obtained as beige-colored crystals in this way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][P:14]([CH2:19][CH:20]1[CH2:22][O:21]1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH2:16]([O:15][P:14]([CH2:19][CH:20]([OH:21])[CH2:22][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:18])[O:13][CH2:11][CH3:12])[CH3:17]
Reactant: Cc1cc([Mg]Br)ccc1F
Reactant: CCOP(=O)(CC1CO1)OCC
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(O)Cc1ccc(F)c(C)c1)OCC
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
To a solution of 4-fluoro-3-methylphenylmagnesium bromide (0.5M in Et2O, 15.5 mL, 7.75 mmol) in THF (10 mL) at −30° C. was added copper (I) iodide, CuI (196 mg, 1.03 mmol) and the reaction mixture was stirred for 10 minutes. The reaction mixture was warmed to −15° C. and oxiranylmethyl-phosphonic acid diethyl ester (1 g, 5.2 mmol) in THF (10 mL) was added. The reaction mixture was stirred at 0° C. for 2 h. Saturated aqueous ammonium chloride was added and the product was extracted into EtOAc. The organic solution was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (20% EtOAc in hexanes to 70% EtOAc in hexanes) provided [3-(4-fluoro-3-methyl-phenyl)-2-hydroxy-propyl]-phosphonic acid diethyl ester (1.37 g).
Reaction SMILES: C(OC([C@@H:8]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1)[CH2:9][N:10]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:33]([O-:35])=[O:34])=[C:20]([CH:22](C(OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[N:13][N:12]=1)=O)(C)(C)C.[Cl-].[Li+].[OH2:56].CS(C)=O>[Cl-].[Na+].O.CCOC(C)=O>[C:39]([O:38][C:36]([N:10]([CH2:9][C@@H:8]([NH:10][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:56])[CH2:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]([F:52])([F:53])[F:51])=[CH:48][CH:49]=1)[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:33]([O-:35])=[O:34])=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[N:13][N:12]=1)=[O:37])([CH3:41])([CH3:42])[CH3:40]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Reactant: O
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a 500 mL round bottom flask was added diethyl 2-(5-(5-((S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propyl-boc-amino)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)malonate (3.60 g, 4.60 mmol), lithium chloride (0.390 g, 9.21 mmol), distilled water (0.0830 g, 4.60 mmol) and 50 mL DMSO. The reaction mixture was heated to 100° C. and stirred at this temperature for 3 hours. LC-MS indicated the reaction was not complete. Another 4 equivalents of LiCl was added. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to ambient temperature, and 200 mL EtOAc and 200 mL brine were added. The organic portion was separated. The aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine and dried over sodium sulfate. The crude mixture (3.40 g) was used in the following reaction without further purification.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:15][CH2:14][CH2:13][C:10]1([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1)(=[O:19])=[O:18]
Reactant: O=C(OC1(CCO)CC1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a mixture of 1-(2-hydroxyethyl)cyclopropyl benzoate (320 mg, 1.55 mmol) and TEA (235 mg, 2.33 mmol, Shantou Xilong chemical factory) in 20 mL of dry CH2Cl2, was added MsCl (213 mg, 1.86 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe at rt. After stirring for 2 hrs at rt, the mixture was diluted with icewater and extracted with CH2Cl2 (30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a pale yellow solid (400 mg, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:3]=1[CH:4]=[N:5]O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([O:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:3]=1[C:4]#[N:5])(=[O:22])[CH3:21]
Reactant: CCCCCCCCCc1ccc(O)c(C=NO)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CCCCCCCCCc1ccc(OC(C)=O)c(C#N)c1
Reaction time: 1 h

Procedure:
A solution of 52.6 parts of 2-hydroxy-5-nonyl-benzaldoxime (in which the nonyl group is a mixture of branched chain isomers; prepared as described in Example 1 of Belgian Pat. No. 796835) in 60 parts of acetic anhydride was stirred and boiled for 1 hour. The cooled solution was poured into water, stirred for 30 minutes and extracted into 2 × 150 parts of chloroform. The extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated at 50° C under vacuum to yield 61.6 parts of 2-acetoxy-5-nonylbenzonitrile as a brown oil. The 61.6 parts of the acetoxy compound were mixed with 200 parts of ethanol and 300 parts of a 2N solution of sodium hydroxide and the mixture stirred and boiled under reflux for 11/2 hours. The cooled solution was acidified with hydrochloric acid, diluted with water and extracted into chloroform. The extracts were water washed, dried over anhydrous magnesium sulphate and evaporated to give 53.1 parts of 2-hydroxy-5-nonylbenzonitrile as a brown oil.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH2:6])=[O:5])[NH2:3].[F:7][CH:8]([F:12])[C:9](O)=O>C1(C)C=CC=CC=1>[F:7][CH:8]([F:12])[C:9]1[NH:6][C:4](=[O:5])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N)C(N)=O
Reactant: O=C(O)C(F)F
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.5 %

Procedure:
20 ml of toluene was added to 500 mg (5.61 mmol) of 2-methyl semicarbazide (produced in the same manner as in Reference Production Example 6), and to this mixture was added 808 mg (8.41 mmol) of difluoroacetic acid, and the mixture was stirred for 10 hours under reflux with heating. The reaction solution was cooled to room temperature, then, concentrated, and the residue was subjected to silica gel thin layer chromatography (eluant: chloroform/methanol=9/1 (v/v)), to obtain 305 mg of 5-difluoromethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one having a melting point of 141.2° C. in the form of colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18]([CH3:19])=[O:32])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)ncn2Cc1ccc2nc(SC)oc2c1
Solvent: ClCCl
Product: COc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)oc2c1
Yield: 63.5 %

Procedure:
A solution of 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methyl thio)benzo[d]oxazole (683 mg, 2.1 mmol) and m-CPBA (471 mg, 2.7 mmol) in DCM (10 mL) was stirred at 0° C. for 3.5 h. The reaction mixture was washed with aq Na2S2O3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 petroleum ether/ethyl acetate to give 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (455 mg, 63.6%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.88 (m, 2H), 7.44 (m, 2H), 7.18 (s, 1H), 6.83 (s, 1H), 5.63 (s, 2H), 3.75 (s, 3H), 3.18 (s, 3H). LCMS (ESI) m/z 342 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[Na].[CH2:22]([SH:24])[CH3:23].CN(C=O)C>O>[CH2:22]([S:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1)[CH3:23]
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Reactant: CCS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Yield: 90.4 %

Procedure:
A mixture of 0.25 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 0.11 g of ethyl mercaptan sodium salt and 3.5 ml of DMF was stirred under ice-cooling for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.26 g of 3-ethylthio-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 12”).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.CO.[OH-].[Na+].OO>O>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
A one-liter flask equipped with a thermometer, stirrer and condenser is charged with 50 g 6,13-dihydroquinacridone, 250 ml methanol, 36 ml water, 0.6 g phthalimidomethyl quinacridone as crystal phase director and particle size reducing agent and 75 g 50% aqueous sodium hydroxide. The mixture is stirred under a slow flow of nitrogen at reflux temperature for one hour generating the corresponding 6,13-dihydroquinacridone-di-sodium salt. 1.2 g 2,7-anthraquinone-disulfonic acid sodium salt is added and the resulting mixture is further stirred at reflux for 10 minutes. Subsequently, 91.4 g of an aqueous 17% hydrogen peroxide solution are added at a rate of 0.3 ml/minute maintaining reflux temperature under a slow nitrogen flow. The resulting bright red suspension is diluted with 100 ml cold water, stirred for 5 minutes and then filtered at 50–60° C. The presscake is washed with hot water then dried yielding a high chroma red gamma quinacridone pigment, which shows less than 100 ppm catalyst residues when analyzed by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:18]([CH3:20])[CH3:19])=[C:16]=[O:17])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH:18]([CH:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:16]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])=[O:17])([CH3:20])[CH3:19]
Reactant: CC(C)C(=C=O)c1ccc(Cl)cc1
Reactant: CC(O)CN(C)C
Solvent: Cc1ccccc1
Product: CC(CN(C)C)OC(=O)C(c1ccc(Cl)cc1)C(C)C
Reaction time: 1.25 h

Procedure:
A 1 dram vial fitted with a septum cap was charged with 0.69 g of toluene followed by 1.08 g of optically-active 1-(dimethylamino)-2-propanol. The resulting mixture was chilled with ice and then 0.196 g of (4-chlorophenyl)isopropylketene was injected. The reaction temperature rose slowly to 30° C. The color discharged after 1.25 hours at room temperature. The reaction product was separated by gas liquid chromatography to give the desired product in a diastereomer ratio of 25.6% of isomer pair 1 and 74.4% of isomer pair 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12](#[N:16])/[CH:13]=[CH:14]/[CH3:15].Cl>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9](=[O:11])[CH3:10])[CH:14]([CH3:15])[CH2:13][C:12]#[N:16])=[CH:6][CH:7]=1
Reactant: C/C=C/C#N
Reactant: CC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(=O)C(c1ccc(Cl)cc1)C(C)CC#N
Temperature: 65 °C

Procedure:
Triton B (5.85 ml) was added dropwise to 4-chlorophenylacetone (21.8 grams) in 78 ml of tert. butanol. Next crotononitrile (9.17 grams) was likewise added with initial cooling to lower the temperature to about 20° C. Since the reaction was not exothermic, no additional cooling was necessary after the desired temperature was reached. The reaction was then heated to 65° C. for 21/2 hours and, after chilling in an ice bath, 262 ml of 1 N HCl was added in portions. Next the reaction mixture was extracted with ether, washed with water, dried, and evaporated in vacuo. An oil resulted which was distilled under vacuum, yield 18.6 grams, b.p. 130°-131° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][NH2:10])[N:4]=1.[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13]>C(O)C>[NH2:15][C:11]1[CH:12]([CH3:14])[CH2:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[N:4]=2)[N:10]=1
Reactant: NNc1cccc(Cl)n1
Reactant: C=C(C)C#N
Agent: [Na]
Solvent: CCO
Product: CC1CN(c2cccc(Cl)n2)N=C1N

Procedure:
As for Example 2 a 0.32 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 10.0 g. of 2-chloro-6-hydrazinopyridine is added, followed by 4.8 g. of methacrylonitrile in place of acrylonitrile. The procedure of Example 2 is followed to give 9.4 g. of crude product. The material is recrystallized from dichloromethane-hexane to give the product of the Example as pale yellow crystals, m.p. 175°-176° C.