Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([S:13][CH3:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]1=[O:21])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([S:13]([CH3:14])=[O:30])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]1=[O:21])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCn1c(=O)c(-c2ccccc2)cc2cnc(SC)nc21
Solvent: ClCCl
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(S(C)=O)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 8-ethyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (127 mg, 0.43 mmol) in dichloromethane (2 mL) was added 3-chloroperbenzoic acid (70%, 95 mg, 0.38 mmol) at 0-5° C. and the mixture was stirred at room temperature for 18 h. The reaction was diluted with dichloromethane (5 mL) and washed with saturated sodium bicarbonate solution (1×3 mL) then with water (1×3 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to get 8-ethyl-2-(methylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one as a pale yellow solid (120 mg, 0.38 mmol, 88%). ESMS m/z 314 (M+H)+.
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+].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Clc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(Cl)cccc21
Yield: 66 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 4-chloro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 247 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [OH-].[Na+:2].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19]/[C:20](=[N:29]\[O:30][CH3:31])/[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19]/[C:20](=[N:29]\[O:30][CH3:31])/[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O-:36])=[O:35].[Na+:2]
Reactant: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)[O-])c(F)c2)cc1)c1ccc(OC)cc1
Yield: 79 %

Procedure:
Compound 47 was synthesized from sodium hydroxide (0.007 g, 0.18 mmol) and 3-{2-fluoro-4-[(4-{[(2Z)-2-(methoxyimino)-2-(4-methoxyphenyl)ethyl]oxy}benzyl)oxy]phenyl}propanoic acid (0.087 g, 0.18 mmol) by following the procedure described in scheme 12 (0.07 g, yield: 79.00%); Purity: 99.79%.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([N:36]=[N+:37]=[N-:38])[C@@H:24]([CH3:39])[CH2:23]1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[C:48]1[N:53]=[C:52]([C:54](O)=[O:55])[CH:51]=[CH:50][C:49]=1[F:57]>CN(C=O)C.O>[N:36]([C@H:25]1[C@@H:24]([CH3:39])[CH2:23][C@@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:54](=[O:55])[C:52]2[CH:51]=[CH:50][C:49]([F:57])=[C:48]([C:42]3[C:41]([F:40])=[CH:46][CH:45]=[CH:44][C:43]=3[F:47])[N:53]=2)[CH2:27][C@H:26]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N+:37]=[N-:38]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
EDC (2.0 equiv.) and HOAt (2.0 equiv.) was added to a solution of tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-azido-3-methylcyclohexylcarbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.08 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl (1R,2S,3S,5R)-2-azido-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate 59% yield. LC/MS (m/z)=582.3 (MH+), Rt=0.97 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:20])([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1.C(Cl)(Cl)Cl>O>[C:21]([O:18][CH2:17][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][CH:11]=1)([OH:20])[CH3:19])(=[O:23])[CH3:22]
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A mixture of 3 g. of 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, 5 ml. of acetic anhydride and 8 ml. of pyridine is allowed to stand for 15 hours at 20°, poured into ice water and worked up with chloroform and water to give 1-acetoxy-3-(2',4'-difluoro-4-biphenylyl)butan-3-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Nc1cc(-c2ccc(F)c(Cl)c2)nc(Cl)n1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3nc(N)cc(-c4ccc(F)c(Cl)c4)n3)cc2)CC1
Yield: 84 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-6-(3-chloro-4-fluorophenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 84% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 214.2 [M+2H]2+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[N:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CO.[C].[Pd]>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1cc2cccnc2cc1CCN1CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)NCCC2
Reaction time: 10 h
Yield: 101.9 %

Procedure:
445 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxyquinoline was dissolved in 10 ml of methanol. Thereafter, 100 mg of 10% palladium carbon was added to the reaction solution. The obtained mixture was stirred for 6 hours under a 4 kg/cm2 of hydrogen atmosphere. Thereafter, palladium carbon was removed by filtration, and the filtrate was concentrated under a reduced pressure. The reaction solution was stirred under the same above conditions for 10 hours 3 times, and then, it was concentrated under a reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 459 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline. This compound was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Na+].[Na+].[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1cc2cccnc2c(Br)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-amino-8-bromo-1,7-naphthyridine (4 g, 0.018 mol) in a mixture of tetrahydrofuran (80 ml) and aqueous Na2CO3 (34 ml, 2N) is added bis(dibenzylideneacetone)palladium (0.40 g, 0.0007 mol), triphenylphosphene (0.37 g, 0.0014 mol) and 3-nitrophenylboronic acid (3.7 g, 0.022 mol). The mixture is stirred for 16 h at 80° C. The mixture is filtered, ethyl acetate added and the mixture washed with 2N NaOH and water. The organic solvent is removed and the residue suspended in ether. Filtration affords the title compound. Mass M+H 267. mp 221-223° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH2:28][CH2:29][NH:30][C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)=[O:32]>>[OH:27][CH2:28][CH2:29][NH:30][C:31](=[O:32])[C:33]1[CH:40]=[CH:39][C:36]([C:37]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(C(=O)NCCO)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: O=C(NCCO)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 227 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(2-hydroxyethyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C27H27N5O3: 470.22; found: 469.58.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.Cl[CH2:43][C:44]([NH2:46])=[O:45].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:18][CH2:19][N:20]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:21][CH2:22]2)=[CH:5][N:4]([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CC(N)=O)CC3)c2c1
Temperature: 115 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
A mixture of 54 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187, 9.4 mg 2-chloroacetamide, 16 mg potassium carbonate and 3 mL dimethylformamide was stirred at 115° C. for 5 hours. 3 mg of 2-chloroacetamide was added thereto, and the mixture was stirred at the same temperature for 3 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, then washed twice with water and then with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 41 mg of the title compound as a colorless amorphous.
Reaction SMILES: C([NH:14][CH:15]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[P:16]([OH:18])[OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[P:16]([OH:18])[OH:17]
Reactant: OP(O)C(NC(c1ccccc1)c1ccccc1)c1ccco1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC(c1ccco1)P(O)O

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-1-(fur-2-yl)-methanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-1-(fur-2-yl)-methanephosphonous acid, melting point 221°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](I)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:26][C:27]([N:29]([O:31]C)C)=O)=[CH:21][CH:20]=1.Cl.NO.C([O-])(O)=O.[Na+]>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:26]/[C:27](/[C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[N:29]\[OH:31])=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Clc1ccc2c(I)ccnc2c1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Product: Cc1ccccc1C(C/C(=N\O)c1ccnc2cc(Cl)ccc12)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 1, 7-chloro-4-iodoquinoline was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4). The product of this reaction could not be obtained pure and was reacted in analogy to example 151, step 3, with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=478.9 [M−H]−.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[F:22])=[CH:7][CH:8]=3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: NCc1ccccc1F
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccccc4F)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 2-fluorobenzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13. Purity by LC/MS=94%, [M+H]+=395.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:11])=S)[CH:6]=[CH:5][N:4]=1>CO.[Ni]>[CH2:2]([C:3]1[CH:8]=[C:7]([CH2:9][NH2:11])[CH:6]=[CH:5][N:4]=1)[CH3:1]
Reactant: CCc1cc(C(N)=S)ccn1
Agent: [Ni]
Solvent: CO
Product: CCc1cc(CN)ccn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-ethyl-4-thiopyridylamide (10 g) in MeOH (250 ml) was added Raney 2800 Nickel (5 g, Aldrich) in one portion. The mixture was stirred at RT for 2 days then at 60° C. for 16 h. The mixture was filtered, concentrated to provide the desired compound.
Reaction SMILES: [CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:8][O:9][CH3:10])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][O:7][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:8][O:9][CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCC(CO)(CCCC)COC
Product: CCCCC(CCCC)(COC)CO[Si](C)(C)C(C)(C)C

Procedure:
According to the procedure as described in Example 8,2,2-di-n-butyl-1-methoxy-3-[(tert-butyldimethylsilyl)oxy]propane was prepared from intermediate 2,2-di-n-butyl-3-methoxy-1-propanol and reagent tert-butyidimethylsilyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1.[F:21][CH:22]([F:24])Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:22]([N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[F:24]
Reactant: FC(F)Cl
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(c2nc(C)nc3ccccc23)C(F)F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (100 mg, 0.35 mmol) in 3 mL of dimethylformamide in a 15 mL high pressure reaction vessel was cooled to −78° C. Diflurochloromethane (about 0.8 mL) was condensed into the solution, then cesium carbonate (160 mg, 0.49 mmol) was added. The reaction vessel was capped and heated at 80° C. overnight. The reaction mixture was cooled to room temperature and cooled to −78° C. and the seal tube was uncapped, warm to room temperature and allowed to stand for 2 h. The reaction mixture was diluted with 50 mL of ethyl acetate and the organic layer was washed with water (50 mL×3), followed by saturated aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexane, 6 drops triethylamine/500 mL of solvent) to give the title compound (35 mg, 0.111 mmol, 32%). 1H NMR (CDCl3): 8.35 (dd, J=1.8, 8.1, 1H), 7.35-(m, 3H), 7.25 (t, J=72.1, 1H), 7.21-7.25 (m, 2H), 6.86-6.91 (m, 2H), 3.82 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([N+:24]([O-])=O)[CH:23]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:23]=[C:22]([NH2:24])[CH:21]=2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(COc2ccc(-c3ccccc3)cc2)cc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Nc1cc(N)cc(COc2ccc(-c3ccccc3)cc2)c1

Procedure:
2.65 g of 4-(3,5-dinitro-benzyloxy)-biphenyl in 30 ml of ethyl acetate were exhaustively hydrogenated in a hydrogen atmosphere with the addition of 200 mg of platinum oxide. Subsequently, the reaction mixture was filtered over Dicalite and the filtrate was concentrated. The residue was recrystallized from ether/hexane and yielded 5-(biphenyl-4-yloxymethyl)-benzene-1,3-diamine in the form of colourless crystals, MS: m/z 290 ([M]+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18](I)=[CH:19][C:12]=3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[Na+].C(=O)([O-])O.[Na+].N>[Cu](I)I.C1(C)C(C)=CC=CC=1.CN1C(=O)CCC1>[CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])=[CH:19][C:12]=3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCSc1cccnc1-c1nc2cc(I)ccc2n1C
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: N
Agent: O=C([O-])O
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: CCSc1cccnc1-c1nc2cc(C(F)(F)C(F)(F)F)ccc2n1C
Temperature: 160 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A mixture of 2-(3-ethylsulfanyl-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (340 mg), copper iodide (410 mg), sodium pentafluoropropionate (800 mg), NMP (5 ml), and xylene (5 ml) was stirred at 160° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous sodium hydrogen carbonate solution and 26% ammonia solution were poured thereto. Then, the mixture was extracted with t-butylmethyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfanyl-pyridin-2-yl)-1-methyl-5-pentafluoroethyl-1H-benzimidazole (240 mg), which is hereinafter referred to as “the present compound 26”.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:2]1.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:16]=1.C(N(CC)CC)C>O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:3]2[O:4][CH2:5][CH2:6][N:1]([C:15]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[N:16]=3)[CH2:2]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 54.3 %

Procedure:
A solution of 4-((2S)-morpholin-2-yl)phenylamine (0.17 g, 0.95 mmol), 2-chloro-3-methyl-4-oxo-6-(pyridin-4-yl)-3,4-dihydropyrimidine (0.17 g, 0.76 mmol), and triethylamine (0.25 g, 2.85 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford 2-[(2S)-2-(4-aminophenyl)morpholin-4-yl]-3-methyl-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (0.15 g, 54%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Yield: 75.4 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)ethanone (14.6 g, 50 mmol) in 210 mL of chloroform and 826 mL of CCl4. A solution of 8.0 g (50 mmol) of bromine in CCl4 was added dropwise to the mixture. When the loss of the bromine colour was complete, the organic layer was washed with 5% aqueous sodium bicarbonate solution and with brine. It was dried over anhydrous sodium sulfate. The drying agent was filtered, and the filtrate concentrated in vacuum to give 14.0 g (70%) of the desired product as a solid.