Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[S:11][C:12]([C:27]([NH2:29])=[O:28])=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.ClC1SC(C(N)=O)=C(OCC2C=CC=CC=2C(F)(F)[F:45])N=1.FC1C=CC2N=CNC=2C=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:45][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][N:1]([C:10]3[S:11][C:12]([C:27]([NH2:29])=[O:28])=[C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:26])([F:25])[F:24])[N:14]=3)[C:5]=2[CH:6]=1
Reactant: NC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Reactant: NC(=O)c1sc(-n2cnc3ccccc32)nc1OCc1ccccc1C(F)(F)F
Agent: Fc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(F)cc32)nc1OCc1ccccc1C(F)(F)F

Procedure:
Following the procedure described above for the preparation of 2-(1H-benzimidazol-1-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide using the following materials: 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide (0.050 g, 0.14 mmol), 5-fluorobenzimidazole (0.011 g, 0.08 mmol), K2CO3 (0.011 g, 0.08 mmol) and DMF (4 mL). Data for 6 regioisomers: 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.82-7.74 (m, 2H), 7.69-7.58 (m, 3H), 7.54-7.50 (m, 1H), 7.16 (td, J=9.1, 2.4 Hz, 1H), 6.80 (bs, 1H), 5.82 (s, 2H), 5.76 (bs, 1H). MS m/z 437 (m+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-dimethoxyaniline (59 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (36 mg, 50%). 1H NMR (DMSO-d6): 9.65 (s, 1H), 8.76–8.73 (m, 1H), 8.32 (d, J=7.8 Hz, 2H), 8.03–7.97 (m, 1H), 7.58–7.54 (m, 2H), 7.05 (d, J=9.0 Hz, 1H), 6.70 (dd, J=3.0, 8.7 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C@@H:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([N:32]3[CH2:31][CH2:30][NH:29][C@H:28]([CH3:27])[CH2:33]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Product: C[C@@H]1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CCN1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.18 mmol) was used in general procedure 3 with (R)-2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give (R)—N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 450.4 (M)+
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([Cl:26])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[Cl:26][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
A mixture of methyl(4-chloro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (1.9 g), 1N NaOH (10 mL), THF (10 mL) and MeOH (10 mL) was stirred at room temperature for 4 h. To the mixture were added 1N HCl (10 mL) and water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual solid was washed with hexane to give the crystals (1.75 g). The crystals were recrystallized from acetone-heptane to give the title compound.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([CH2:22][CH2:21][CH2:20][CH2:19][NH2:23])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(CCCCN)CC(C)(C)N1OC1CCCCC1

Procedure:
The product is prepared analogously to the method described in Example II-1, by reaction of 126.7 g (0.5 moles) of 1-cyclohexyloxy-2,2,6,6-tetramethyl-4-oxopiperidine and 38.4 g (0.52 moles) of n-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[C:9]([C:10]([NH:21][C@H:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)[CH3:23])=[O:12])=[CH:13][C:14]([F:17])=[CH:15][N:16]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(F)cnc1COc1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2COc2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 2-[(4-chlorophenoxy)methyl]-5-fluoronicotinic acid (step 5) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]=[O:14])[CH:12]=1)[O:9][C:8]([CH3:16])([CH3:15])[CH2:7][C:6]2([CH3:18])[CH3:17])#[CH:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([CH:13]=[O:14])[CH:12]=2)[O:9][C:8]([CH3:16])([CH3:15])[CH2:7][C:6]3([CH3:18])[CH3:17])=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C=O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure J and using 6-ethynyl-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Compound 44, 0.39 g, 1.61 mmol), 4-iodo phenyl acetic acid methyl ester (0.444 g, 1.61 mmol), triethyl amine (10 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.090 g, 0.13 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent the title compound was obtained as an oil (0.5 g, 80%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3]O.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>>[CH3:5][C:2]1([CH3:6])[CH2:3][CH2:7][S:8](=[O:10])(=[O:9])[NH:1]1
Reactant: CC(C)(N)CO
Reactant: CS(=O)(=O)Cl
Product: CC1(C)CCS(=O)(=O)N1

Procedure:
Using 2-amino-2-methyl-1-propanol (1.5 g) and methanesulfonyl chloride (2.7 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (130 mg) was obtained.
Reaction SMILES: [C:1]12([C:11]3[C:12](=[O:22])[NH:13][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.I[CH3:24]>CN(C=O)C>[C:1]12([C:11]3[C:12](=[O:22])[N:13]([CH3:24])[N:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CI
Reactant: O=c1[nH]n(-c2ccccc2)cc1C12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C23CC4CC(CC(C4)C2)C3)cn1-c1ccccc1
Reaction time: 16 h
Yield: 0.1 %

Procedure:
A sealable tube was charged with 4-adamantan-1-yl-1-phenyl-1,2-dihydro-pyrazol-3-one (0.05 g), iodomethane (0.036 g) and DMF (1 mL) and purged with argon and sealed. The reaction vessel was immersed into a heated oil bath at 110 degrees C. for 16 hours. The reaction vessel was then cooled and opened carefully. The reaction mixture was diluted with EtOAc and aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted with further EtOAc and the combined organic layers were washed with sodium thiosulfate. The phases were then dried over sodium sulfate, filtered and reduced in vacuo. The crude gum was chromatographed by adsorption onto silica gel and subjection to Isco Combiflash chromatography. Evaporation of the desired fractions afforded the desired product 4-adamantan-1-yl-2-methyl-1-phenyl-1,2-dihydro-pyrazol-3-one (0.035 mg) as a white solid. MS (ESI+): 309.4 [M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]([C:31]1([CH2:36][CH3:37])[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30]>>[CH2:29]([C:31]1([CH2:36][CH3:37])[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32]1)[CH3:30]
Reactant: CCC1(CC)CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: CCC1(CC)CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3,3-diethylpyrrolidine via General Procedure E to give 26.5 mg of 301 following reverse phase purification. MS (Q1) 4892 (M)+
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:8]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])=[N:9][C:10]([CH3:19])=[N:11][C:12]=1[O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[C:30](=[O:32])=[O:31]>C1COCC1>[CH2:15]([CH:14]([O:13][C:12]1[C:7]([C:30]([OH:32])=[O:31])=[C:8]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[N:9]=[C:10]([CH3:19])[N:11]=1)[CH2:17][CH3:18])[CH3:16]
Reactant: O=C=O
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-BuLi in THF was added a solution of [5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine in THF at −78° C. After stirring for 10 minutes, CO2(g) was added at −78° C. and stirred at that temperature for 1 hour, then gradually warmed to room temperature. The resulting mixture was quenched with water and adjusted to pH 2 to 3 and extracted with chloroform. The organic layer was separated, dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound as a solid, mp. 118–120° C., Anal. For C20H27N3O3 calc.: C, 67.20; H, 7.61; N, 11.76; found: C, 67.25; H, 7.87; N, 11.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([CH2:17]O)([CH2:15]O)[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]2[O:10][CH2:14][C:13]([CH3:17])([CH3:15])[CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(CO)CO
Product: CC1(C)COB(c2ccc(F)c(Cl)c2)OC1
Yield: 80 %

Procedure:
The title compound (80%, crystalsl) was prepared from 3-chloro-4-fluorophenylboronic acid and neopentylglycol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]Cl.[C-:11]#[N:12].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a vigorously stirred solution of 3,5-dichlorobenzylchloride (28 g) in dichloromethane (150 ml) was added a mixture of KCN (27.5 g) and tetrabutylammonium hydrogen sulphate (2.38 g) in water (110 ml). After stirring at room temperature for 22 hours, the mixture was diluted with dichloromethane, the organic phase washed with water and concentrated in vacuo to leave an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH3:18])([CH3:17])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH3:16])=[O:8]>ClCCl.CCCCCCC>[CH3:17][CH:6]1[CH2:18][C:14]2[C:9](=[C:10]([CH3:16])[CH:11]=[C:12]([CH3:15])[CH:13]=2)[C:7]1=[O:8]
Reactant: Cc1ccc(C(=O)C(C)(C)Cl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (38 g, 0.29 mole) was suspended in 200 ml of anhydrous dichloromethane. 2-Chloro-2,2′,4′-trimethylpropiophenone (30.0 g, 0.14 mole) in 30 ml of heptane was slowly added to this suspension. During the addition (30 min) the temperature was kept at room temperature. After the addition was completed, the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was poured onto 400 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of crude 2,5,7-trimethyl-1-indanone was 22.9 g or 92%. A sample was crystallized from pentane to give crystalline material.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=4)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=3)[N:3]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)cc1
Yield: 56.5 %

Procedure:
Following general procedure II, 6-chloro-N-{4-[(dimethylamino)methyl]phenyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (50 mg, 0.14 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (35 mg, 42%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 8.47 (d, J=9.1 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.59-7.52 (m, 2H), 7.34 (s, 2H), 4.43 (s, 2H), 3.48 (s, 3H), 2.86 (s, 6H); ESI MS m/z 517 [M+H]+; HPLC>99% (AUC), tR=11.03 min.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(OCC)(=O)C>[C:24]([C:23]1[CH:22]=[C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: N#Cc1cccc(N)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 35.4 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 6 ml of water and 1 ml of ethyl acetate in place of the methanol, and 118 mg of 3-aminobenzonitrile in place of the 3-(tert-butyl)aniline. 120 mg of N-(3-cyanophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][S:5][C:4]1=[C:8]([C:14](=[O:23])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([O:11]CC)=O.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>CN(C)C=O>[CH2:16]([N:15]1[C:14](=[O:23])[C:8](=[C:4]2[S:3][CH:7]=[CH:6][S:5]2)[C:9](=[O:11])[CH:25]([C:24]([O:28][CH2:29][CH3:30])=[O:27])[CH2:26]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)=C1SC=CS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Sodium hydride (a 60% dispersion in oil) (1.50 g) is suspended in N,N-dimethylformamide (100 ml) and a solution of ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (10.0 g) in dimethylformamide (250 ml) is added dropwise thereto at 4° to 5° C. The mixture is stirred at the same temperature for 30 minutes. A solution of ethyl acrylate (4.1 ml) in dimethylformamide (100 ml) is added dropwise to the mixture, and the mixture is stirred at the same temperature for one hour and then at room temperature for 5 hours. The mixture is poured into ice-water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is recrystallized from a mixture of n-hexane and ethyl acetate, whereby ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-3-carboxylate (8.76 g ) is obtained as pale yellow needles. Yield: 75%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[NH3:9]>>[NH3:3].[NH2:9][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)ncn1
Agent: N
Product: Cc1cc(N)ncn1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-6-methylpyrimidine (Recl. Trav. Chim. Pays-Bas. 84; 1965, 1101-1106) (1 g, 7.81 mmol) and 0.88 ammonia (25 mL) were heated in a sealed vessel at 100° C. for 18 hours. The cooled mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to give the title compound, 560 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([SH:14])[CH3:13]>>[NH2:1][C:2]1[N:7]=[C:6]([S:14][CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCS
Product: CCSc1nc(N)ccc1[N+](=O)[O-]

Procedure:
6-Amino-2-chloro-3-nitropyridine was allowed to react with ethanethiol to give 6-amino-2-ethylthio-3-nitropyridine (m.p. 131.5°-132° C.). The product was then treated with acetic anhydride to give 6-acetylamino-2-ethylthio-3-nitro-pyridine (m.p. 167.5°-168° C.). The nitro group of this product was reduced in a usual manner to the amino group. The amino compound, without purification, was dissolved in 42% tetrafluoroboric acid, and then diazotized by addition of sodium nitrite to give 6-acetylamino-2-ethylthio-3-pyridine-diazonium fluoroborate decomposing at 132°-133° C. The diazonium salt was subjected to Schiemann reaction under reflux in petroleum benzine. The reaction product was isolated and purified in a usual manner to give 6-acetylamino-2-ethylthio-3-fluoro-pyridine (m.p. 110°-113.5° C.). Then the product was allowed to react with ethyl ethoxymethylenemalonate to give diethyl N-(2-ethylthio-3-fluoro-6-pyridinyl)aminomethylenemalonate (m.p. 77.5°-78.5° C.), which was subjected to cyclization reaction to give ethyl 7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 280°-284° C.). The 1,8-naphthyridine derivative thus obtained was treated with 2-fluoroethyl p-toluenesulfonate to give ethyl 7-ethylthio-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 271°-273° C.), which was then oxidized with m-chloroperbenzoic acid to give ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 176°-178° C.).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])[C:9]([C:16]([OH:18])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])[C:9]([C:16]([Cl:21])=[O:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Reactant: O=S(Cl)Cl
Product: Cn1c(=O)c(C(=O)Cl)nn(-c2ccccc2)c1=O
Yield: 87.5 %

Procedure:
Intermediate e (3 g, 0.012 mol) was added to thionyl chloride (10 V/W, 30 mL). The mixture was warmed up to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (2.8 g) in a yield of 87.5%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:40]1[N:41]=[C:42]([NH:45][C:46]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[S:43][CH:44]=1)[C:10]([NH:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:17]([CH2:20][Cl:21])[CH2:18][S:19][C@H:14]12)=[O:11].ClC1C=CC=C(C(OO)=[O:73])C=1.O>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:40]1[N:41]=[C:42]([NH:45][C:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[S:43][CH:44]=1)[C:10]([NH:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:17]([CH2:20][Cl:21])[CH2:18][S:19](=[O:73])[C@H:14]12)=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (6.5 g) in ethyl acetate (40 ml) was added dropwise a solution of m-chloroperbenzoic acid (1.54 g) in ethyl acetate (10 ml) at 0° C. The mixture was stirred for two hours under ice-cooling and then poured into a mixture of ethyl acetate (50 ml) and water (100 ml). The organic layer was washed with brine and then dried. The solvent was evaporated in vacuo and the residue was pulverized with diisopropyl ether to give benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (6.90 g).