Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.[CH:36](=O)[CH3:37].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:36][CH3:37])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(Cl)c(Cl)c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(5-(3,4-dichlorobenzylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide (2.0 g) as starting compound, acetaldehyde (0.27 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 0.82 g of 4-amino-5-chloro-N-((1-(5-(N-(3,4-dichlorobenzyl)-N-ethylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1.S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27]>O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([N+:26]([O-:28])=[O:27])[C:16]([CH3:20])=[N:15]1
Reactant: Cc1cc(C)n(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)-3,5-dimethylpyrazole (31.9 g) was added 95% sulfuric acid (35 ml) and then added dropwise an acid mixture of 95% sulfuric acid (7.5 ml) and 61% nitric acid (10.3 g) under cooling with iced water, and the reaction mixture was stirred at room temperature for further one hour, and was then poured into iced water. The reaction mixture was extracted with toluene and the resulting toluene layer was washed with 1N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent from.the extract in toluene by distillation in vacuo gave the titled compound (33.1 g) as a yellowish brown crystalline solid. Recrystallization of the solid from a mixture of cyclohexane/acetone yielded a pale yellow crystalline solid. m.p. 150.5°-152.5° C.
Reaction SMILES: [SeH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:5]=[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])[CH2:3][CH2:2][Se:1][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC[SeH]
Solvent: c1ccncc1
Product: O=C([Se]CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reaction time: 3 h

Procedure:
To a chilled solution of 0.5 g. of 1-(3-selenyl-1-oxopropyl)-L-proline dissolved in 5 ml. of pyridine there is added dropwise with stirring 0.3 g. of benzoyl chloride. The mixture is allowed to come to room temperature. After three hours, the solvent is evaporated. The residue is taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and then with water. The solvent is dried, and evaporated to yield 1-[1-oxo-3-[(benzoyl)-selenyl]propyl]-L-proline.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH3:19]O>>[N+:6]([C:9]1[CH:17]=[C:13]([C:14]([O:16][CH3:19])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reaction time: 8 h

Procedure:
80 ml of methanol and 10 g of concentrated sulfuric acid were added to 5 g of 5-nitrosalicylic acid. The resultant mixture was heated under stirring for 8 hours while distilling methanol off. The solvent was then distilled off under reduced pressure and the residue was dissolved in chloroform. The resultant chloroform solution was washed with water and then concentrated to dryness. The resultant residue was purified by chromatography on a silica gel column (eluent: chloroform), followed by recrystallization from chloroform-ether to obtain 5.1 g of methyl 5-nitrosalicylate as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH:12]1([CH2:18][C@H:19]([N:23]2[C:27](=[O:28])[C@H:26]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[NH:25][C:24]2=[O:36])[C:20](O)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:21])[C@@H:19]([N:23]2[C:27](=[O:28])[C@H:26]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[NH:25][C:24]2=[O:36])[CH2:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[N:3][CH:4]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)nc1

Procedure:
By using the conditions described in Step (iv) of Example 17, methyl 6-aminonicotinate was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd for C26H36N4O5 (M+) 485.2764, found 485.2768.
Reaction SMILES: [ClH:1].C([Cl:5])(=O)C.[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[ClH:5].[ClH:1].[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Reaction time: 0.17 h

Procedure:
To a solution of 2.4 mmol of HCl in 2 mL of methanol (prepared by the addition of 0.17 mL of acetyl chloride at 0° C. and stirring for 10 min) was added 90 mg of 4-(N-(benzyloxycarbonyl)-N-(prop-1-yl)amino)-1-t-butoxycarbonylpiperidine. The mixture was stirred at rt for 16 h at which time the reaction was complete by TLC (20% ethyl acetate/hexanes) and was evaporated to dryness in vacuo to afford 75 mg of the title compound as the di-hydrochloride salt and which was used in the above reductive alkylations.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]([C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[N:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]3=[CH:14][N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cccn2c(-c3ccc(F)cc3)ncc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccn2c(-c3ccc(F)cc3)ncc12
Temperature: 25 °C

Procedure:
To a solution of 3-(4-fluorophenyl)-imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (290 mg, 1.0 mmol) in methanol (20 mL) is added a solution of 85% potassium hydroxide pellets (0.300 g, 3.92 mmol) in water (5.0 mL). The reaction mixture is warmed at reflux for 5 minutes, cooled to room temperature and concentrated in vacuo to remove excess methanol. The mixture is acidified to pH 4 with 1 N aqueous HCl and the resulting precipitate is collected by filtration, washed with water and dried to afford the title product.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1c(F)ccc(F)c1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(F)c(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,6-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.26-7.35 (m, J=9.4, 9.4, 3.8, 2.0 Hz, 1H), 7.62-7.77 (m, 2H), 8.57 (dt, J=8.0, 1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 9.30 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 278 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].Cl>CC#N.O1CCOCC1>[Cl:32][C:33]1[C:34]([F:40])=[C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]4[CH2:18][CH2:17][NH:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 60 °C
Yield: 68.6 %

Procedure:
1-tert-butyl 2-methyl (2S,4R)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (12) (0.45 g, 1.0 mmol) was dissolved in MeCN (11 ml) under nitrogen. 3-Chloro-2-fluoroaniline (153 mg, 1.05 mmol) was then added followed by 4M HCl in dioxane (1.2 ml). The resulting mixture was heated overnight at 60° C. The reaction mixture was cooled to −8° C. and the resulting solids collected by filtration and washed with diethylether. The solids were dissolved in methanol, loaded onto an SCX column and eluted with methanol followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) as a clear gum (316 mg, 69%): 1H NMR Spectrum: (DMSO-d6) δ1.45-1.58 (2H, m), 2.02-2.11 (1H, m), 2.32-2.40 (1H, m), 2.57-2.67 (1H, m), 3.08-3.13 (1H, m), 3.42-3.48 (1H, m), 3.64 (3H, s), 3.95 (3H, s), 4.54-4.64 (1H, m), 7.05-7.10 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.48-7.57 (2H, m), 7.85 (1H, s), 8.38 (1H, s), 9.56 (1H, s); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][C:22]([S:25]([C:28]2[S:32][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:36]1[CH2:35][CH2:34][N:33]([C:31]2[S:32][C:28]([S:25]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)(=[O:26])=[O:27])=[CH:29][N:30]=2)[CH2:38][CH2:37]1)=[O:9])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccncc1)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccncc3)s2)CC1
Yield: 32 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light red crystalline solid (yield 32%). MS (m/e): 551.2 (M+H+, 100%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:14][CH:15](Cl)[C:16](=O)[CH3:17]>C1(C)C(C)=CC=CC=1>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[O:12][CH:17]=1
Reactant: CSc1ccc(C=CC(N)=O)cc1
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1C
Product: CSc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
2.00 g (10.3 mmol) 3-(4-methylsulfanyl-phenyl)-acrylamide, 2.63 g (22.0 mmol) dichloro acetone and 60.0 ml xylene were kept at reflux temperature for 3 h with continuous removal of water by use of a Dean-Stark trap (a water separator used in chemical reactions). After removal of solvents in vacuo, the residue was partitioned between ethyl acetate and water. The organic extracts were dried and the solvent was distilled off. The remaining residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 1:3). Yield: 1.50 g (55%) 4-Chloromethyl-2-[2-(4-methylsulfanyl-phenyl)-vinyl]-oxazole as a light yellow solid melting at 126-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:41]1([C:48]([C:50]2[CH:55]=[CH:54][C:53](Br)=[C:52]([CH3:57])[CH:51]=2)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([C:48]([C:50]2[CH:55]=[CH:54][C:53]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[C:52]([CH3:57])[CH:51]=2)=[O:49])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)N2CCCCCC2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCCCCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and azepan-1-yl-(4-bromo-3-methyl-phenyl)-methanone (41 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of azepan-1-yl-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-272) as a pale brown powder (16 mg, 33%).
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].C(=O)(O)[O-].[Na+]>>[Cl:13][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[C:6]([CH3:10])[N:5]=1
Reactant: Cc1cc(C)c(C#N)c(O)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)c(C#N)c(Cl)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A stirred mixture of 3-cyano-4,6-dimethyl-2-hydroxypyridine (4.35 g, 29.39 mmol) and phosphorous pentachloride (6.92 g, 33.21 mmol) is heated to 120° C. The reaction mixture becomes clear and is stirred for an additional 1 hr. It is then poured onto ice/water (250 mL) and allowed to stand for 30 min. The solution is neutralized with sodium bicarbonate (pH 6) and extracted with dichloromethane (400 mL). The separated organic layer is dried, filtered and concentrated to yield 2-chloro-3-cyano-4,6-dimethylpyridine (4.60 g, 94% yield) as a tan solid containing ca 15% impurity. LC/MS: MS m/e=167/169 (M+H); RT 2.98 min; NMR (CDCl3, δ ppm) 7.08 (1H, s), 2.57 (3H, s), 2.55 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C1(C2[O:21]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11]([CH3:12])=[O:21])[N:3]=1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)c1nc(N)nc(Cl)c1C#N
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred suspension of 2.00 g (9.97 mmol) 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile in 6 ml dichloromethane and 20 ml DMF was added 5.21 g (19.9 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue recrystallised from ether/dichloromethane to afford 1.50 g (69%) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 239 (M+Na+, 45), 234 (M+NH4+, 55), 217 (M+H+, 100).
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:8]([C:17]([OH:19])=O)=[C:7]([CH3:20])[NH:6][C:5]1=[O:21])(=[O:3])[NH2:2].[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:32]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][CH2:30][NH:31][C:17]([C:8]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[N:4]([C:1](=[O:3])[NH2:2])[C:5](=[O:21])[NH:6][C:7]=2[CH3:20])=[O:19])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)N(C(N)=O)C(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N(C(N)=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
102 mg (0.329 mmol) of 3-carbamoyl-4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 83.5 mg (0.395 mmol) of (3,3-diphenylpropyl)amine were dissolved in 10 ml of DMF. 94.6 mg (0.494 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.[Br-:16]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:16][CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: [Br-]
Reactant: CCCCCC(=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(Br)C(=O)c1ccc(OC)cc1
Yield: 93.4 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-methoxy-phenyl)-hexan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. The crude product obtained was distilled under a reduced pressure and purified by a silica gel column chromatography eluted with petroleum ether and ethyl acetate (20:1) to give a product as a white solid in a yield of 93.4%, mp: 54-55 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.92 (3H, t, J=7.2 Hz, CH3), 1.30˜1.60 (4H, m, CH2CH2), 2.05˜2.25 (2H, m, CH2CHBr), 3.89 (3H, s, OCH3), 5.11 (1H, t, J=7.2 Hz, CHBr), 6.96 (2H, d, J=8.80 Hz, ArH), 8.01 (2H, d, J=8.80 Hz, ArH); ESI-MS m/e (%): 286.1 (M+2, 2), 284.1 (M, 2), 230.0 (3), 228.0 (3), 205.1 (5), 135.1 (100).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 70 °C
Yield: 56.7 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (49.9 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 70° C. for over-night. The solvent was evaporated and the residue was crystallized from EtOAc-hexanes to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (50 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.O=[C:15]([CH3:23])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21]>C1C=CC=CC=1>[C:20]([NH:19][CH2:18][CH2:17][CH2:16][C:15]1([CH3:23])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)(=[O:22])[CH3:21]
Reactant: Cc1cn(CCO)c2ccccc12
Reactant: CC(=O)CCCNC(C)=O
Solvent: c1ccccc1
Product: CC(=O)NCCCC1(C)OCCn2c1c(C)c1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-methylindole-1-ethanol (4.2 g.) and N-(4-oxopentyl) acetamide (3.7 g), described by L. P. Khun et al., J. Am. Chem. Soc., 89, 3858 (1967), in 300 ml of dry benzene is stirred and heated at reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated to yield 1-[3-(acetamido)propyl]-1,10-dimethyl-3,4-dihydro-1H- 1,4-oxazino[4,3-a]indole γ maxCHCl3 1650 cm-1.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20]>CN(C)C=O.O>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
Sodium hydride (1.51 g, 62.92 mmol, 2.00 equiv) was added in small portions to a solution of phenol (3.25 g, 34.53 mmol, 1.10 equiv) in N,N-dimethylformamide (50 mL) maintained under nitrogen at 0-5° C. After stirring for 30 min at 0-5° C., 1,2-difluoro-4-nitrobenzene (5 g, 31.43 mmol, 1.00 equiv) was added. The reaction mixture was stirred overnight at room temperature and then diluted with 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×150 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-2% ethyl acetate in petroleum ether to afford 3.2 g (44%) of 2-fluoro-4-nitro-1-phenoxybenzene as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.46-7.41 (m, 2H), 7.30-7.26 (m, 1H), 7.12-7.04 (m, 2H), 7.02-6.93 (m, 1H) ppm.