Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(OCC)C>[N:21]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][CH:18]=[C:12]3[C:13]([NH:15][C:16](=[O:17])[C:11]=23)=[O:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCCCCN3CCCC3)cccc21

Procedure:
8-Bromooctylphthalimide (517 mg; 2.0 mmoles) and pyrrolidine (0.33 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[CH:21](I)([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:22][CH:21]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 50 °C

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (3 g), isopropyl iodide (3.2 ml) and K2CO3 (2.94 g) were combined in acetonitrile (70 ml) and the reaction mixture heated at 50° C. overnight. The reaction was allowed to cool to room temperature, filtered and evaporated. The residue was dissolved in diethylether (50 ml) and washed successively with water (50 ml), saturated sodium thiosulphate solution (50 ml), saturated brine (50 ml) and dried (Na2SO4). The solvent was evaporated to give the title compound (D3) as a pale yellow oil (3.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:17][O:18][CH2:19][C:20]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)=[O:21]
Reactant: COCC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Solvent: c1ccncc1
Product: COCC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 79 %

Procedure:
3-(2-Methoxy-acetyl)-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with 2-methoxy-acetic acid chloride in pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1.O[N:29]1[C:33]2C=[CH:35][CH:36]=[CH:37][C:32]=2N=N1.N1CCCCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([N:29]3[CH2:35][CH2:36][CH2:37][CH2:32][CH2:33]3)=[O:22])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1
Reactant: Cc1nnc2n1-c1sc(CCC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1nnc2n1-c1sc(CCC(=O)N3CCCCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a solution of 1.1 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.25 g of piperidine and stirred at room temperature for 10 minutes. To the mixture is added 0.65 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 20 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 50 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from ethyl acetate. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 0.9 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4 ]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid piperidide as colorless crystals, melting at 157°-160° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Li])CCC.CCCCCC.CI.P([O-])(O)(O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH3:23])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: Cc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.30 g) was dissolved in tetrahydrofuran (10 ml), and a solution of n-butyllithium/n-hexane (1.56M, 1.4 ml) was added dropwise thereto at -70° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture for 10 minutes. Then, methyl iodide (0.09 ml) was added dropwise to the reaction mixture, and the resulting mixture was stirred for 10 minutes. After the temperature of the reaction mixture was raised to 0° C., the reaction mixture was poured into ice-cold water, and an aqueous potassium dihydrogenphosphate solution was added to the mixture to adjust the pH to a value of 6. Then, the mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous NaCl solution, followed by drying over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (0.29 g, 94%) as a colorless powder.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2O.P(Cl)(Cl)([Cl:18])=O>>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[Cl:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2c(OC(F)F)cccc12
Product: FC(F)Oc1cccc2c(Cl)ccnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from step b) was heated to reflux in phosphorus oxychloride (80 ml) for 1 hour. The reagent was evaporated under reduced pressure to give an oil which was carefully poured into a mixture of ice/880 ammonia solution (400 ml) and stirred for 30 minutes. The solid was filtered off and dried in vacuo to give the sub-title compound (6.80 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[C:14](F)=[CH:13][CH:12]=[CH:11][C:10]=2Cl)[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C([N-]C(C)C)(C)C.[Li+].C(OCC)(=O)C.CCCCCC>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Fc1cccc(Cl)c1-c1cc(Cl)nc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1ccc(Nc2cc(-c3ccccc3)nc(Cl)n2)cc1

Procedure:
To 1 mmol of 2,4-dichloro-6-phenylpyrimidine (X) and 4-chloroaniline in 4 mL of dry THF was added 1 mmol (0.5 mL, 2M in THF/heptane/ethylbenzene) of lithium diisopropylamide. The reaction was followed by TLC (30% ethyl acetate/hexane). The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The mixture was purified by chromatography on silica gel with elution by 30% ethyl acetate/hexanes to afford 70 mg of 2-chloro-N-(4-chlorophenyl)-6-phenylpyrimidin-4-amine (XII) as an amorphous solid. ESI/MS 315.883, 317.915 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15].O>O1CCCC1.CN(C)C=O>[O:13]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3][CH2:2][O:1][C:18](=[O:19])[NH:17][CH:14]([CH3:16])[CH3:15])[NH:8]1
Reactant: CC(C)N=C=O
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)OCCc1cccc2c1CC(=O)N2
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (3 g, 16.93 mmol) and isopropyl isocyanate (2.49 mL, 25.40 mmol) in tetrahydrofuran (16 mL) and dimethylformamide (6 mL) was heated at 80° C. for 64 hours. The reaction mixture was poured into water and extracted with ethyl acetate (400 mL), washed with brine, dried (sodium sulfate), and concentrated. The residue was recrystallized form methanol, ethyl acetate and hexanes to give 1.136 g (26%) of isopropyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as crystalline solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1I)[CH3:2].[F-].[Cs+]>COCCOC.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>[NH2:3][C:11]1[CH:6]=[CH:7][C:8]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[C:6]([C:5]=2[C:14]#[N:15])=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)=[CH:9][CH:10]=1
Reactant: CCn1c(I)c(C#N)c2ccc(OC)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 137.1 %

Procedure:
A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetramethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90 mmol), CsF (1.46 g, 9.58 mmol) and Pd(PPh3)2Cl2 (110 mg, 0.15 mmol) in DME (20 mL) is added to a flask and alternatively evacuated and flushed with N2. The reaction is then heated at reflux for 24 h and then cooled to room temperature. The reaction mixture is diluted with H2O and extracted with EtOAc (2×). The combined organic phases are washed with H2O and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is purified by flash chromatography on silica gel using EtOAc/CH2Cl2 (5/95) as eluent to afford 765 mg (69%) of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.Br.C1C=C[NH+]=CC=1.[Br:16][Br-]Br>CC(O)=O>[Br:16][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1csc(Br)c1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Thiophene-3-formic acid (12.6 g) and AcOH (96 ml) are added to a reaction flask (250 ml), to dissolved after stirred at room temperature, HBr solution (8 ml) is then added to the reaction flask, and the reaction is rapidly changed to a light yellow. Pyridinium bromide perbromide (27 g) is then added to the flask in batches at room temperature. After addition, the reaction is stirred at room temperature, and the reaction is tracked by HPLC. The above mixture is poured into ice-water after reaction, stirred for about 30 minutes, filtered to form a white powder solid, the white powder solid is crystallized with hot water, filtered and dried to obtain a crystal of 5-bromo-thiophene-3-formic acid (10.8 g), content of 92% measured by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11]([CH3:21])(O)[O:10][N:9]=2)=[CH:4][CH:3]=1.BrC1C=CC(C2C(C3C=CC(SC)=C(F)C=3)C(C)(O)ON=2)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[C:11]([CH3:21])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(O)ON=C(c2ccc(Br)cc2)C1c1cccc(F)c1
Agent: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Product: Cc1onc(-c2ccc(Br)cc2)c1-c1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure of step 2 in the Example 168 using 3-(4-bromophenyl)-4-(3-fluorophenyl)-5-methyl-4,5-dihydro-5-isoxazolol, instead of 3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].Cl[C:36]([O:38][CH3:39])=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([C:36]([O:38][CH3:39])=[O:37])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27](=[O:28])[NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)[CH2:12]1)(=[O:10])=[O:9]
Reactant: COC(=O)Cl
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Product: COC(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) in methylenehloride (0.7 mL) was added under stirring ethyldiisopropyl amine (18.3 μL, 105 μmol) and methyl chloroformate (6.15 μL, 77.0 μmol). The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using a gradient from methylenechloride to a mixture of methylenechloride/methanol (v:v 19:1) as solvent to yield the title compound as a white solid (32 mg, 80%). MS ISP (m/e): 564.3/566.1 (100/40) [(M+H)]+.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:37][C:38]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=4[C:40]([NH2:42])=[O:41])[C:20]4[C:25]([CH3:26])=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[C:25]([CH3:26])[C:20]4=[C:19]([NH:37][C:38]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=4[C:40]([NH2:42])=[O:41])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3c(C)cn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3c(C)cnc-3[nH]1)N(C(=O)CN(C)C)CCC2
Temperature: 120 °C
Yield: 78.4 %

Procedure:
2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (146 mg, 0.208 mmol) was dissolved in dioxane (3 mL) and 2N NaOH (2 mL) was added in a microwave safe vessel. The reaction was then heated in a microwave at 120° C. for 10 min. Reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide (89 mg, 0.163 mmol) as a pink solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.92 (m, 2 H) 2.10 (br. s., 6 H) 2.42 (s, 3 H) 2.67 (br. s., 2 H) 3.20 (s, 2 H) 3.66-3.74 (m, 2 H) 3.84 (s, 3 H) 6.74 (s, 1 H) 6.79-6.86 (m, 1 H) 6.86-6.96 (m, 1 H) 7.31-7.40 (m, 1 H) 7.42 (s, 1 H) 8.12 (d, J=14.92 Hz, 2 H) 8.40 (d, J=8.61 Hz, 2 H) 9.88 (s, 1 H) 10.99-11.11 (m, 1 H). ESIMS (M+H)+=547
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+].[F:19][CH:20]([F:29])[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:19][CH:20]([F:29])[O:21][C:22]1[CH:23]=[C:24]([NH:25][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:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(OC(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)F)c1
Yield: 46.4 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 520 mg of 3-(difluoromethoxy)aniline in place of the 2,4-difluoroaniline. 135 mg of N-[3-(difluoromethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10]1)(=[O:3])[CH3:2].Cl.[CH3:20][O:21][NH2:22].O>CN1CCCC1=O>[C:1]([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:22][O:21][CH3:20])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10]1)(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OCCON=C1Oc2ccccc2C1=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CON=C1C(=NOCCOC(C)=O)Oc2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10 g (0.04 mol) of 2-(3-oxo-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIV-1) and 4.18 g (0.05 mol) of O-methylhydroxylamine hydrochloride are dissolved in 40 ml of N-methyl-2-pyrrolidinone and stirred at 80° C. for 1 hour. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 10.6 g of crude 2-(3-methoxyimino-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIII-1) are obtained, which are chromatographed over silica gel using a mixture of tert-butyl methyl ether and petroleum ether (1:1). 6.9 g (59.1% of theory) of 2-(3-methoxyimino-3H-benzofuran-2-ylideneaminooxy)ethyl acetate (XIII-1) having a content of 82.15% of stereoisomer A and 13.38% of stereoisomer B are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2nncs2)cc1Cl
Yield: 54 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (0.466 g, 0.749 mmol) prepared in Example 86b, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (0.191 g, 54%) as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCN1CCOCC1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine;
Reaction SMILES: [H-].[Na+].C1COCC1.[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13]4=[C:14]([C:25](=[O:35])[C:26]([CH2:28]C5C=NC=CC=5)=[CH:27][N:12]4[C:11]=2[CH:10]=1)[CH:15]=[C:16]([O:23][CH3:24])[CH:17]=3.CI>CS(C)=O.O>[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13]4=[C:14]([C:25](=[O:35])[C:26]([CH3:28])=[CH:27][N:12]4[C:11]=2[CH:10]=1)[CH:15]=[C:16]([O:23][CH3:24])[CH:17]=3
Reactant: COc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COc1cc2c3c(c1)c(=O)c(C)cn3-c1cc(Br)ccc1S2
Temperature: 0 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A solution of sodium hydride(840 mg) in DMSO(200 mL) was stirred at 60-70° C. for 30 min. After addition of THF (60 mL), the mixture was cooled down to 0° C. To the mixture were added dropwise a solution in DMSO of the compound (7g) obtained in Example 36 <step 2>, then methyl iodide (1.33 mL). After stirring for 1 hour, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was suspended in dioxane (5 mL) and to the suspension was added DDQ (1.22 g). The mixture was heated under reflux for 3 hours. After allowing the reaction mixture to cool to room temperature, IN sodium hydroxide (20 mL) and ethyl acetate (50 mL) were added. The precipitated crystals were collected by filtration and washed with water and ethanol. The resultant compound (1.1 g) was suspended in dioxane (60 mL) and to the suspension was added DDQ (1.2 g). The mixture was heated under reflux for 3 hours. After allowing the reaction mixture to cool to room temperature, to the mixture were added 1N-sodium hydroxide (20 mL) and ethyl acetate(50 mL). The precipitated crystals were collected by filtration and washed with water and ethanol to obtain the title compound (1.1 g; 11%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11](O)=[O:12])[N:6]2[CH:14]=1)[CH3:2].[BH4-].[Na+].Cl.[OH-].[Na+]>>[CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][OH:12])[N:6]2[CH:14]=1)[CH3:2]
Reactant: CCc1cn2c(C(=O)O)cccc2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCc1cn2c(CO)cccc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 5.29 g (24.24 mmol) of ethyl ester of 2-ethylimidazo[1,2-a]pyridine-5-carboxylic acid was added 2.75 g (72.72 mmol) of sodium borohydride under ice-cooling. The reaction mixture was stirred for 3 hours under ice-cooling. The reaction mixture was then poured into 150 ml of ice-water. The reaction mixture was mixed well, to which was added 12N HCl until the pH of the solution reached 2. This solution was stirred for two hours at room temperature, which was neutralized with a 6N aqueous solution of sodium hydroxide. The solvent was completely distilled off under reduced pressure. To the residue was added 200 ml of methanol. The mixture was mixed well, then insolubles were filtered off. The solvent was distilled off under reduced pressure to give 2.99 g of a crude product (70%, white solid). This crude product was used, without purification, in the subsequent reaction.