Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:17][CH:16]=3)[C:12](=[O:31])[NH:11][C:10]=2[CH:32]=1.CO.[C:44]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@H:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:19][CH:20]=3)[C:12](=[O:31])[N:11]([CH3:44])[C:10]=2[CH:32]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)NC(=O)[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc2c(c1)N(C)C(=O)[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionic acid methyl ester (9.5 mmol) was dissolved in 60 mL THF-DCM (1:1) and methanol (14.2 mmol) and resin-bound triphenylphosphine (14.2 mmol) was added. The mixture was cooled to 0° C. and DIAD (14.2 mmol) added. The mixture was agitated for 10 min at 0° C. and the mixture was slowly allowed to warm up to r.t. and agitated for 16 h. The reaction mixture was filtered, concentrated and the residue purified over silica-gel hexanes-ethyl acetate (8-2) to afford (S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionic acid methyl ester. (4.9 g). 1H NMR (400 MHz, CDCl3): 7.51 (d, 1H), 7.44 (d, 1H), 7.31 (m, 2H), 7.25 (m, 1H), 6.96-6.88 (m, 3H), 6.74 (m, 2H), 5.63 (s, 1H), 5.03 (m, 1H), 4.98 (s, 2 h), 4.58 (m, 1 h), 3.70 (s, 3H), 3.41 (s, 3H), 3.05 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[S:16])[NH2:15])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>CC(C)=O>[Cl:17][CH2:18][C:19]1[N:15]=[C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]([S:5][C:2]([F:1])([F:4])[F:3])=[CH:11][CH:10]=2)[S:16][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)C=Cc1ccc(SC(F)(F)F)cc1
Solvent: CC(C)=O
Product: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)cs2)cc1
Yield: 70.5 %

Procedure:
2.00 g (7.6 mmol) 3-(4-trifluoromethylsulfanyl-phenyl)-acrylthioamide, 2.90 g (22.8 mmol) 1,3-dichloroacetone and 60 ml acetone were stirred at room temperature for 4 days, then refluxed for 4 h. The product was precipitated by addition of water, isolated and dried, and purified on silica. Elution with ethyl acetate/heptane 1:1 yielded 1.80 g (71%) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-thiazole as yellow solid, melting at 133-134° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2ccccc2OC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-n1ncc(C(=O)O)c1C
Yield: 85 %

Procedure:
To a solution of ethyl 5-methyl-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxylate in 15 ml methanol and 17 ml water was added 20 ml of 1 N sodium hydroxide and the resulting mixture was refluxed overnight under nitrogen. The methanol was removed in vacuo and the aqueous phase was acidified with dilute aqueous hydrochloric acid solution and extracted with 2×70 ml ethyl acetate. The combined ethyl acetate extracts were washed with 70 ml water and 70 ml brine, dried over sodium sulfate and concentrated in vacuo to a white solid (2.14 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([C:12](OC)=[O:13])[CH:8]=[C:9]([CH3:11])[CH:10]=2)[N:6]=1.CC(C[AlH]CC(C)C)C>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][OH:13])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(C)cc2sc(N)nc12
Agent: CC(C)C[AlH]CC(C)C
Product: Cc1cc(CO)c2nc(N)sc2c1

Procedure:
30 g (0.135 mol) of 5a are reduced with 337.7 ml (0.405 mol) of DIBAL (20% strength solution in toluene) in analogy to Example 1a.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)([CH3:12])([CH3:11])[CH3:10].[BH4-].[Na+]>CC#N>[C:9]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccn1
Reactant: CC(C)(C)Oc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)Oc1ccccc1CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
2-(Aminomethyl)pyridine (0.849 g, 7.85 mmol) and 8 (1.4 g, 7.8 mmol) were added to 150 mL of CH3CN and the reaction mixture was refluxed under argon for 4 hr. After cooling down to room temperature, the solvent was removed and the residue was redissolved in MeOH. The solvent was then evaporated and NaBH4 (1.485 g, 39 mmol) was added and stirred overnight. The solvent was evaporated, followed by extraction with CH2Cl2. The CH2Cl2 extract was concentrated and purified by a silica gel column using 3% methanolic NH3 (7 M NH3 in methanol/97% CH2Cl2 as eluent to yield the desired product as a pale yellow oil (58%). 1H NMR (CDCl3) δ 8.530 (m, 1H, Ar), 7.604 (ddd, 1H, Ar), 7.330 (m, 2H, Ar), 7.128 (m, 2H, Ar), 7.027 (d, 2H, Ar), 6.969 (ddd, 1H, Ar), 3.892 (s, 2H, —CH2—), 3.837 (s, 2H, —CH2—), 2.523 (s, 1H, —CH—), 1.373 (s, 9H, —C(CH3)3). Mass Spec.=271.18 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].C([Li])CCC.[CH3:12][N:13]1[C:21]2[N:20]=[CH:19][N:18]([CH2:22][CH2:23][CH3:24])[C:17]=2[C:16](=[O:25])[N:15]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[C:14]1=[O:31].C(Cl)(Cl)Cl>CCCCCC.O1CCCC1>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]#[C:6][C:28]([OH:30])([CH3:29])[CH2:27][CH2:26][N:15]1[C:16](=[O:25])[C:17]2[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[N:20][C:21]=2[N:13]([CH3:12])[C:14]1=[O:31]
Reactant: CCCn1cnc2c1c(=O)n(CCC(C)=O)c(=O)n2C
Reactant: C#CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCCn1cnc2c1c(=O)n(CCC(C)(O)C#CCN(C)C)c(=O)n2C

Procedure:
4.32 g (52 mmol) of N,N-dimethyl-2-propynylamine, 32.4 ml (52 mmol) of n-butyllithium as 1.6 M solution in n-hexane and 11.1 g (40 mmol) of 3-methyl-1-(3-oxobutyl)-7-propylxanthine were reacted in tetrahydrofuran and worked up in analogy to Example 1C2), but using chloroform in place of dichloromethane as extractant.
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[S:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][N:18]=2)[C:11](=[O:13])[O-])=CC=1)([O-])=O.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(#N)C>[CH:19]([C:16]1[S:15][C:14]([NH:10][C:11]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([I:22])[CH:24]=2)=[O:13])=[N:18][CH:17]=1)([CH3:20])[CH3:21]
Reactant: CC(C)c1cnc(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)s1
Reactant: Nc1cccc(I)c1
Solvent: CC#N
Product: CC(C)c1cnc(NC(=O)Nc2cccc(I)c2)s1
Temperature: 70 °C
Yield: 73.3 %

Procedure:
1 g (3.25 mmol) of 4-nitrophenyl-5-isopropyl-1,3-thiazol-2-ylcarbamate and 0.39 ml (3.25 mmol) of 3-iodoaniline were suspended under argon in 25 ml of acetonitrile. After 2 hours at 70° C. the resulting solution was cooled, giving rise 0.923 g of the title compound, recrystallized from a mixture of diethylether/pentane 1/1.
Reaction SMILES: Br[C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:7]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:20]([NH:27][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(NCc2ccccc2)cc1-n1ccnc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
A solution of 1-[5-bromo-2-nitro-4-(trifluoromethyl)phenyl]-1H-imidazole (580 mg; 1.73 mmol; 1 eq) prepared as in example 52 step 2, benzylamine (210 μl; 1.9 mmol; 1.1 eq) and diisopropylethylamine (331 μl; 1.9 mmol; 1.1 eq) in anhydrous acetonitrile is stirred at 60° C. for 16 h. Concentration, partition (ethyl acetate/aqueous ammonium chloride), extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulfate), concentration and purification by prep CCM on silicagel (dichloromethane/ethyl acetate 50:50) affords the title product (200 mg; 0.552 mmol; 32%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]([CH3:22])[CH3:21]>C(Cl)(Cl)Cl>[CH2:19]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CO
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)[C@H](CC(C)C)NC(=O)Cc1ccccc1
Reaction time: 96 h

Procedure:
N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL CHCl3 (EtOH free) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure to an oil which was sufficiently pure for testing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22]
Reactant: CCCCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[hydroxy-(4-butoxy-phenyl)-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 74 mg of the title compound. 1H NMR (CDCl3) δ 0.95 (t, 3H, J=7.31 Hz), 1.50 (m, 2H), 1.80 (m, 2H), 4.05 (t, 2H, J=6.48 Hz), 5.15 (s, 2H), 6.95 (d, 2H, J=9.04 Hz), 7.65 (d, 1H, J=8.22), 7.80 (d, 2H, J=9.04 Hz), 7.90 (dd, 1h, J=1.88, 7.91), 8.45 (d, 1H, J=1.88). MS (m/z): 368 (M+1). CHN Calc C, 55.51; H, 4.93; N, 3.81. Found C, 55.47; H, 4.84; N, 3.63.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:9]2[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[C:6]([CH3:8])[N:7]=1)[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OC(=O)C)C>[CH2:1]([C:3]1[NH:4][C:5]([C:9]2[CH:14]=[C:13]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCc1nc(C)c(-c2cc(F)ccc2[N+](=O)[O-])[nH]1
Solvent: CCOC(C)=O
Product: CCc1nc(C)c(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])[nH]1

Procedure:
5 g 2-(2-Ethyl-4-methyl-imidazolyl)-4-fluoro-nitrobenzene and 10 g piperidine were heated 30 minutes at 100° C. After cooling 150 ml ethylacetate were added. The solution was extracted three times with 50 ml water. The organic layer was evaporated to dryness. The residue is purified by chromatography (silica gel, dichloromethane/methanol=95/5).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([CH2:12][N:13]([C@:20]2([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH2:31][CH2:32][CH3:33])([OH:23])[C@@H:21]2[OH:34])[C:14](=[O:19])[NH:15][CH2:16][CH2:17][Cl:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[N+:36]([O-])([N+]([O-])=O)=[O:37].CCCCCC>O1CCCC1.C(O)(=O)C>[CH:6]1([CH2:12][N:13]([C@:20]2([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH2:31][CH2:32][CH3:33])([OH:23])[C@@H:21]2[OH:34])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][Cl:18])[N:36]=[O:37])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCC[C@]1(O)O[C@H](CO)[C@@H](O)[C@@](O)(N(CC2CCCCC2)C(=O)NCCCl)[C@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@]1(O)O[C@H](CO)[C@@H](O)[C@@](O)(N(CC2CCCCC2)C(=O)N(CCCl)N=O)[C@H]1O
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
Anhydrous sodium acetate (15 g) was added to a solution of 3-cyclohexylmethyl-3-(n-butyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)urea (3.94 g, 9.02 mmol) in a mixture of tetrahydrofuran (120 ml) and acetic acid (20 ml), and dinitrogen tetraoxide gas (4 g) was introduced into the mixture with well stirring at 0° to 5° C. spending 5 minutes. After the mixture was stirred at the same temperature for further 30 minutes to complete reaction, n-hexane (200 ml) was added and insoluble matter was filtered off. The filtrate was vacuum-concentrated at 25° C. and fractionated by column chromatography (packing: silica gel; eluent: ethyl acetate/chloroform/methanol (2:10:1) to isolate the objective product. Thus, 1.62 g of 3-cyclohexylmethyl-3-(n-butyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained; yield 38.5%, m.p. 75°-77° C., [α]D20 +47.2° (C 1.0, methanol).
Reaction SMILES: CN1CCN(C)C1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)=[O:18])[CH:10]=1.[C:30]1([NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].CS(O)(=O)=O>O>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:37][C:25](=[O:27])[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17]([O:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[O:18])=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Reactant: Nc1ccccc1N
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: Nc1ccccc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
7.78 g (48 mmole) of N,N′-carbonyldiimidazole were added to a 1,3-dimethyl-2-imidazolidinone (50 g) suspension including 11.45 g (40 mmole) of 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic acid. After stirring at room temperature for 2 hours, 17.30 g (0.16 mole) of 1,2-phenylenediamine were added to the solution. After cooling to 2° C., 9.60 g (0.1 mole) of methanesulfonic acid were added dropwise. After stirring for 2 hours, water was added, and the deposited solid was collected by filtration. Purification was then carried out through silica gel column chromatography to obtain 10.83 g (yield: 72%) of N-(2-aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1-c1ccncc1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 2-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 4-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 4-(2-chloro-phenyl)pyridine was isolated. The yield was 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(C(OCC)=O)[C:15]([O:17]CC)=[O:16])=[CH:12][N:11]=[C:10]1[S:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:15]([OH:17])=[O:16])=[CH:12][N:11]=[C:10]1[S:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCSc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCSc1ncc(C(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]phenylmethyl-malonate (0.66 g, 1.28 mmol), sodium carbonate (1.36 g, 1.28 mmol), ethanol (15 mL) and water (10 mL) was refluxed on a steam bath for 18 hours. The mixture was concentrated to a small volume, some insolubles were filtered, the aqueous layer was washed with diethyl ether and then the aqueous phase was adjusted to pH 3.4 with aqueous hydrochloric acid. The product was extracted into methylene chloride, washed with water, dried and concentrated to give 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-3-phenyl-propionic acid; mp 60°-63° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].C1C(=O)N(Cl)C(=O)C1.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.CCN(CC)CC>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 160.8 %

Procedure:
A mixture of 4-bromo-3-methylbenzaldehyde oxime (384 mg, 0.5 mmol) and NCS (286.7 mg, 2.14 mmol) in DMF (10 mL) was stirred at 40° C. for 40 min. The mixture was cooled to 0° C. and to it was added 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (261 mg, 1.08 mmol) followed by Et3N (0.15 mL). The reaction mixture was stirred at rt for 20 h, poured into water and extracted with EA (10 mL). The organic layer was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel to give 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (364.2 mg; yield 82%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:35])[F:34])=[CH:26][CH:27]=2)[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(C(F)(F)F)cc2)c(=O)n1OCc1ccccc1
Yield: 66.7 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 4-trifluoromethylphenyl isocyanate (1.36 mL, 9.51 mmol) in DMA afforded 1.97 g of the title compound as a solid, mp 245-246° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
To a solution of 3-(4-bromophenyl)-propionic acid (9.16 g, 40 mmol) in THF (150 mL) at 0° C. was added LiAlH4 (1.4 g, 36 mmol) in portionwise. When the addition was completed, the reaction mixture was heated and stirred under reflux for additional 5 hours. The reaction mixture was cooled to 0° C. and 2 N—HCl (50 mL) added dropwise. The reaction mixture was extracted with EtOAc and washed with water (×3). The combined organic extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo, which afforded the subtitle compound (i) as an oil (8 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28](O)=[O:29].O>ClCCl.CN(C)C1C=CN=CC=1>[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Cl:13])=[O:29]
Reactant: O=C(O)C1CCCO1
Reactant: OCCCCCCCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(OCCCCCCCCCl)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5.7 g) in dichloromethane (100 ml) was slowly added to a solution of 8-chloro-1-octanol (4.1 g), tetrahydro-2-furancarboxylic acid (3.5 g) and 4-dimethylaminopyridine (1.5 g) in dichloromethane (50 ml) at 0° C. The mixture was stirred overnight at room temperature. The resulting solution was then added to water (500 ml) and extracted with dichloromethane (3×200 ml). The combined organic layers were washed with water (2×200 ml), dried over magnesium sulphate and filtered. The solvent removed in vacuum. The residue (7 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (90:10) as eluent to give 8-chlorooctyl tetrahydro-2-furancarboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]=2[N:11]=[CH:10][N:9]=1)([CH3:15])[CH3:14]
Reactant: C1CNCCN1
Reactant: CC(C)Sc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: CC(C)Sc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-isopropylthio-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 132°-134° C.) and piperazine.