Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[C:3]([OH:9])[CH:2]=1.Cl.Cl.[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23](O)=O.[OH-].[Na+]>>[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]1[O:9][C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][C:4]=2[N:8]=1
Reactant: Nc1ccc(O)c(N)c1
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2oc(-c3cccc4c(Cl)cccc34)nc2c1
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 79.3 %

Procedure:
80 μmol of 2,4-diaminophenol.2HCl and 80 μmol of 5-chloro-naphthalene-1-carboxylic acid were dissolved in 100 mg of PPA, and then, the mixed solution was stirred at a temperature of 180° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 10% NaOH, and filtered by using distilled water for recrystallization in a slow manner, thereby obtaining 18.7 mg of 2-(5-chloronaphthalene-1-yl)benzo[d]oxazole-5-amine (Derivative #5) (yield: 79%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.S(=O)(=O)(O)O.[F:18][C:19](I)([F:21])[F:20].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[F:18][C:19]([F:21])([F:20])[C:4]1[C:5](=[O:10])[NH:6][C:7](=[O:9])[NH:8][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: O=c1[nH]c(C(F)(F)F)c(C(F)(F)F)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
0.18 g (1.0 mmol) of 6-trifluoromethyluracil and 0.058 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 60 to 70° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5,6-bis(trifluoromethyl)uracil (19F-NMR yield: 63%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5,6-Bis(trifluoromethyl)uracil was obtained as a white solid (0.12 g, yield: 48%) by preparative thin-layer chromatography.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(Cl)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3-chloroaniline (50.8 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (99 mg, 84%). 1H NMR (CDCl3): 8.59 (d, J=4.2 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.80 (br, 1H), 7.67 (t, J=1.5 Hz, 1H), 7.38 (s, 1H), 7.19 (m, 1H), 7.10 (m, 2H), 6.91 (m, 1H), 6.41 (s, 1H), 2.28 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15].Br[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:8]2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[F:15]
Reactant: BrC1CCCC1
Reactant: COC(=O)c1c[nH]c2cc(Br)c(F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C2CCCC2)c2cc(Br)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of methyl 6-bromo-5-fluoro-1H-indole-3-carboxylate (9.0 g, 33 mmol), bromocyclopentane (5.3 mL, 49.6 mmol) and Cs2CO3 (21.5 g, 66 mmol) in DMF (40 mL) was stirred at 80° C. overnight. The mixture was then poured into ice water, filtered and washed with water. The solid was collected and dried to give methyl 6-bromo-1-cyclopentyl-5-fluoro-1H-indole-3-carboxylate (10.3 g, yield 91%), which was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].[OH-].[Na+]>C(Cl)Cl>[O:30]([C:28]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[S:20][C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:13]1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccc(CN2CCC3(CC2)c2ccccc2Sc2ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)c1ccccc1Sc1ccccc12
Reaction time: 18 h

Procedure:
To a stirred solution of 1'-benzylthioxanthene-9-spiro-4'-piperidine (2 g.) in methylene chloride (25 ml.) is added dropwise a solution of phenyl chloroformate (0.88 g.) in methylene chloride (15 ml.) at room temperature during 10 minutes. Stirring is continued for 18 hours, the methylene chloride is shaken with 1.ON sodium hydroxide solution, washed with water and dried (Na2SO4). The solution is filtered, the solvent evaporated and the residual oily product is crystallised from ethanol to give 1'-phenoxycarbonyl-thioxanthene-9-spiro-4'-piperidine, m.p. 149°-151° C.
Reaction SMILES: [K+].[P:2]([O-:14])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].Cl.[OH-].C[N+](C)(C)C.C(OP([O-])(OC(C)(C)C)=O)(C)(C)C.C[N+](C)(C)C.[Cl:40][CH2:41]I>CO.C(COC)OC>[P:2]([O:14][CH2:41][Cl:40])([O:4][C:5]([CH3:7])([CH3:8])[CH3:6])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:3]
Reactant: ClCI
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 0 °C

Procedure:
Di-tert-butyl phospohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time, The reaction as then allowed to continue at room temperature for an additional half hour, Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C., a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the elude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield): 1HNMR (CD3OD, 300 MHz) δ 1.51 (s, 12H, 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) δ −11.3 (s, 1 P).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:14]=1)=O)(C)(C)C.C(OC(N1CC=C[C@H]1C(O)=O)=O)(C)(C)C.ClC(OCC(C)C)=O.C(N(CC)CC)C.C(C1C=C(C=CC=1)C(NO)=N)#N>C1COCC1.CN(C=O)C>[NH:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:24]#[N:25])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1c1nc(-c2cccc(C#N)c2)no1
Agent: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#Cc1cccc(C(=N)NO)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2noc([C@@H]3C=CCN3)n2)c1
Temperature: 120 °C

Procedure:
(S)-2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (372 mg, 42%, slightly impure) was prepared according to the procedure in Example 25 from (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester (557.8 mg, 2.62 mmol) with isobutyl chloroformate (0.36 mL, 2.77 mmol) and triethylamine (0.73 mL, 5.2 mmol) in THF (7.5 mL). Then 3-cyano-N-hydroxy-benzamidine (424 mg, 2.6 mmol) and DMF (7 mL) were added and the mixture was heated at 120° C. for 16 h. 1H-NMR (CDCl3) was consistent with the expected product and showing a mixture of rotomers due to the Boc protecting group.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[NH:17][C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12].[CH3:20][CH:21]1[CH2:23][CH:22]1[CH2:24]Br>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[N:17]([CH2:20][CH:21]2[CH2:23][CH:22]2[CH3:24])[C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12]
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2F)[nH]c1C
Reactant: CC1CC1CBr
Product: Cc1cc(C(=O)CCc2ccc(F)cc2F)n(CC2CC2C)c1C
Yield: 80.2 %

Procedure:
The title compound was prepared as a yellow oil in 80.2% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(2,4-difluorophenyl)propionyl]-2,3-dimethylpyrrole and 2-methylcyclopropylmethyl bromide.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:34]([CH:37]([CH2:41][O:42][CH3:43])[CH2:38][O:39][CH3:40])[N:35]=[CH:36][C:10]=13)[CH2:2]2.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:62][N:63]([CH3:65])[NH2:64].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:62][N:63]([CH3:65])[NH:64][C:28]([C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[N:12]=[C:11]4[N:34]([CH:37]([CH2:38][O:39][CH3:40])[CH2:41][O:42][CH3:43])[N:35]=[CH:36][C:10]4=[C:9]([N:3]4[CH2:2][CH:1]5[O:8][CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:14]=3)=[CH:16][CH:17]=2)=[O:33])=[CH:25][CH:26]=1)=[O:30]
Reactant: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)O)cc4)cc3)nc21
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)NN(C)C)cc4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
A mixture of 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ureido)benzoic acid (0.11 g, 0.19 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 51 mg, 0.37 mmol), N-methylmorpholine (63 μL, 0.57 mmol), and N,N-dimethylhydrazine (63 μL, 0.57 mmol) in dimethylformamide (3 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 72 mg, 0.37 mmol). After approximately 20 minutes, additional quantities of N,N-dimethylhydrazine (100 μL) and EDC (100 mg) were added. The mixture was stirred overnight at room temperature and then purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 75% acetonitrile to provide 1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{1-[2-methoxy-1-(methoxymethyl)ethyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)urea (114 mg, 95%). MS (ES+): 630.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:40]=[CH:39][C:20]([C:21]([N:23]([CH3:38])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:38])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:22])=[CH:39][CH:40]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C=CCCCC(=O)O)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CCCCCC(=O)O)cc2)cc1
Yield: 99.6 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-carboxy-1-pentenyl)phenyl]benzamide (150 mg) in ethanol (10 ml) was shaken under hydrogen atmosphere (3 atm.) in the presence of 10% palladium on carbon (50 mg) for 4 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo and the residue was subjected to silica gel column (29% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-carboxypentyl)phenyl]benzamide (150 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:17]>C1(C)C=CC=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.Cl[Pd]Cl>[F:15][C:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][C:5]=1[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
70.6 g (258 mmol) of the above 4-bromo-2-fluoro-N-pivaloylaniline was dissolved in 500 mL of toluene under argon atmosphere, 108 mL (310 mmol) of 1-ethoxyvinyltributyltin and 1.80 g (2.57 mmol) of bis(triphenylphosphine)palladium (II) chloride were added, and the mixture was stirred at 100° C. for 5 hours. The reaction solution was cooled on ice, 500 mL of 2N HCL was added, and the mixture was stirred at room temperature for 2 hours. The insoluble matters were filtered off and the filtrate was extracted once with ethyl acetate. 500 mL of a 10% aqueous solutiuon of ammonium fluoride was added to the organic layer and the mixture was stirred at room temperature for 3 hours. The insoluble matters were filtered off and the organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1-4:1), to give 60.8 g of 3'-fluoro-4'-pivaloylaminoacetophenone (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:29]([C:27]3[S:28][C:24]([Cl:23])=[CH:25][CH:26]=3)=[O:30])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1ccc(Cl)s1

Procedure:
The title compound was prepared by procedure analogous to that described in Example 12 using 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one and 5-Chloro-thiophene-2-carboxylic acid. LCMS observed for (M+H)+: 470.2
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[N:7]=1.[CH2:15]([NH:22][CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:15]([N:22]([CH2:13][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][CH3:11])=[CH:5][N:4]=1)[CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCN(C)c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a solution of 3-chloro-5-[methyl(propyl)amino]pyrazine-2-carbaldehyde (427 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (469 mg) and acetic acid (343 μL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (636 mg), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added dropwise a saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5-*50% ethyl acetate/hexane) to give the title compound (579 mg, 74%).
Reaction SMILES: [CH3:1][O:2][NH2:3].C([O-])([O-])=O.[K+].[K+].[F:10][C:11]1[CH:18]=[C:17]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])[C:20]2=[O:31])[CH:16]=[CH:15][C:12]=1[CH:13]=O.CO>C(COC)OC.C(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[CH:13][C:12]1[CH:15]=[CH:16][C:17]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])[C:20]2=[O:31])=[CH:18][C:11]=1[F:10]
Reactant: CON
Reactant: Cc1ccncc1N1CCN(c2ccc(C=O)c(F)c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CON=Cc1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Temperature: 40 °C
Yield: 9.1 %

Procedure:
O-Methyl-hydroxylamine (84 mg, 1.003 mmol) and K2CO3 (207 mg, 1.5 mmol) were added to a solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde-(I-121a: 300 mg, 1.003 mmol) in dimethoxyethane (10 mL). The resulting mixture was heated to 40° C. for 2 hours. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was filtered, washed with CHCl3 and the filtrate was concentrated under reduced pressure to afford 30 mg of crude 2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde O-methyl-oxime, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:69]1[CH2:73][CH2:72][CH2:71][CH:70]1[CH2:74][NH:75][CH2:76][CH2:77][C:78]#[N:79]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:75]([CH2:76][CH2:77][C:78]#[N:79])[CH2:74][CH:70]2[CH2:71][CH2:72][CH2:73][O:69]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: N#CCCNCC1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)CC2CCCO2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.5 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g), TBTU (0.096 g) and HOBT (0.030 g) in DMF (1 ml) was added DIPEA (0.052 ml) followed by 3-[(tetrahydro-furan-2-ylmethyl)-amino]-propionitrile (0.047 g) after 15 min. The reaction was stirred at room temperature for 96 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.078 g) was obtained as a brown oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:26]([O:28]C)=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]=[O:25])[CH:16]=1)=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:26]([OH:28])=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]=[O:25])[CH:16]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=Cn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)c2ccccc21
Yield: 75.6 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 30 (4.8 g), 1 mol/L of an aqueous sodium hydroxide solution (16 mL), and methanol (160 mL), to give the captioned compound (3.5 g, 75%) as crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[C:14]([F:17])([F:16])[F:15].B(Br)(Br)Br.CO.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[C:14]([F:17])([F:15])[F:16]
Reactant: COc1cccc2c(C(F)(F)F)cc(C)nc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(F)(F)F)c2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of 11 g (45.6.10-3 mol) of 8-methoxy-2-methyl-4-trifluoromethylquinoline in 360 ml of dichloromethane is cooled to -60° C. and 228 ml of a 1 M solution of boron tribromide in dichloromethane are added dropwise. The reaction medium is subsequently stirred for 1 hour at room temperature, 250 ml of methanol are then added slowly and stirring is continued for 2 hours. 250 ml of dichloromethane are added and sodium bicarbonate solution is added to render the medium alkaline. The organic phase is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 8.25 g of the expected product in the form of brown crystals (yield=79.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl.[F:10][C:11]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:15][CH2:16][C:11]([F:17])([F:10])[CH2:12][CH2:13]2)=[CH:7][N:6]=1
Reactant: FC1(F)CCNCC1
Reactant: Brc1cnc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: FC1(F)CCN(c2cnc(Br)cn2)CC1
Yield: 38.2 %

Procedure:
A solution of 2,5-dibromopyrazine (200 mg), 4,4-difluoropiperidine hydrochloride (132 mg) and cesium carbonate (603 mg) in dimethyl sulfoxide (5 mL) was stirred overnight at 90° C. under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (89 mg).