Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Solvent: C1CCOC1
Product: CNc1nc(N(C)c2ccc(OC)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M methylamine in THF (4 ml, 8 mmol) by a procedure similar to example 38 to give 20 mg (30%) of yellow solids. 1H NMR (CDCl3): 8.02-8.01 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.42-7.34 (m, 2H), 6.97-6.94 (m, 1H), 6.76-6.70 (m, 2H), 5.01 (brs, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.12 (d, J=5.1 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[CH:12]=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.O.CN(C)[CH:44]=[O:45]>>[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[C:12]([CH:44]=[O:45])=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24]1
Reactant: CN(C)C=O
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c2c(c(C=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reaction time: 0.08 h

Procedure:
Phosphorus oxychloride (551 μl) was added to dimethylformamide (10 ml) at room temperature and stirred for 5 minutes. A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (502 mg) in N,N-dimethylformamide (1 ml) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (290 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19](/[CH:21]=[C:7]1\[CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3][C:2]\1=[O:1])[CH3:20]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Product: CN(C)/C=C1\CC(NC(=O)OC(C)(C)C)CCC1=O

Procedure:
A solution of tert-butyl 4-oxocyclohexylcarbamate (10 g, 0.046 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (50 mL) was heated at 100° C. for 15 hours. 1,1-dimethoxy-N,N-dimethylmethanamine was then removed under reduced pressure. The crude desired product, (E)-tert-butyl 3-((dimethylamino)methylene)-4-oxocyclohexylcarbamate obtained as an oil was used in the next reaction without any purification. LCMS [M+H}: 269.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 19.5 h

Procedure:
To a solution of 4-hydroxy-3-nitrobenzoic acid (10.0 g) in methanol (100 ml), concentrated sulfuric acid (1 ml) was added and stirred at 80° C. for 19.5 hours. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate and ethyl acetate were added to the resulting residue. This mixture was stirred and the aqueous layer was then separated. The separated aqueous layer was diluted with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give methyl 4-hydroxy-3-nitrobenzoate (10.9 g) as a yellow solid. To a solution of methyl 4-hydroxy-3-nitrobenzoate thus obtained (10.9 g) in tetrahydrofuran:methanol (1:1, 100 ml), 10% palladium on activated carbon (550 mg) was added and stirred overnight under a hydrogen atmosphere at room temperature. After the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure to give methyl 3-amino-4-hydroxybenzoate (9.1 g) as a light-brown solid. To a solution of methyl 3-amino-4-hydroxybenzoate thus obtained (9.1 g) in N,N-dimethylformamide (80 ml), potassium carbonate (37.3 g) and 1,2-dibromoethane (14 ml) were added and stirred at 130° C. for 2 hours and then stirred overnight at room temperature. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and washed with water. The organic layer was extracted with 6M aqueous hydrochloric acid, and the resulting aqueous layer was diluted with 8M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 5:1) to give the titled compound, i.e., methyl 3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (7.10 g) as a pink solid.
Reaction SMILES: [C:1]([Cu])#[N:2].[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10](I)[C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[CH2:5][CH2:6][CH3:7]>N1C=CC=CC=1.C(Cl)Cl>[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:1]#[N:2])[C:9]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([I:23])=[CH:21][CH:22]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1nc(C)nc(I)c1Cc1ccc(I)cc1
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc(C)nc(C#N)c1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
A mixture of 800 mg (8.94 mmol) CuCN and 10 mL pyridine was heated to 110° C. until all of the CuCN went into solution (7 minutes). To this mixture was added a solution of 440 mg (0.894 mmol) 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine in 3 mL pyridine. After 5 minutes, the reaction mixture was cooled to room temperature, diluted with CH2Cl2, filtered through powdered cellulose flock, stripped of solvent in vacuo, and was medium pressure chromatographed on silica gel using 13% EtOAc/hexane to give 306 mg of the title compound, 87% yield. Rf 0.29 in 15% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain; 1H-NMR (300 MHz, CDCl3): δ 7.63 (m, 2H), 6.84 (m, 2H), 4.16 (s, 2H), 2.73 (s, 3H), 2.68 (3 line m, 2 H), 1.53 (m, 2H), 1.31 (m, 2H), 0.87 (3 line m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:28][CH:27]=2)[CH:10]([CH2:44][OH:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:46](Br)[CH:47]=[CH2:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:30][CH:31]=2)[CH:10]([CH2:44][O:45][CH2:48][CH:47]=[CH2:46])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: C=CCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 13 (g), by alkylating (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [WO 9709311, Example 148 (h)] with allylbromide there was obtained (3SR,4RS,5RS)-3-allyloxymethyl-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-( naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid; MS: 652 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21]([CH:22]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18]3)[N:12]3[N:19]=[CH:20][C:21]([CH:22]=[C:30]4[NH:24][C:25](=[O:26])[NH:27][C:28]4=[O:29])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Nc3cccc(Cl)c3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To 5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (26 mg, 0.08 mmol) in EtOH was added hydantoin (8 mg, 0.08 mmol) and piperidine (8 μl, 0.08 mmol). The mixture was stirred at 70° C. for 3 days. Insolubles were filtered off, and filtrate was concentrated under reduced pressure. Filtrate was then dissolved in methanol and purified by HPLC to yield 5-((5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=410)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])(=[O:17])C.[NH4+]>C(O)(=O)C>[Cl:14][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:17])[C:11]=1[C:12]#[N:13]
Reactant: CC(=O)[O-]
Reactant: N#Cc1c(Cl)nc2ccccc2c1Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Temperature: 25 °C
Yield: 76.6 %

Procedure:
2,4-dichloroquinoline-3-carbonitrile (Example 72a) (0.95 g, 4.26 mmol) and ammonium acetate (0.36 g, 4.67 mmol) were heated in acetic acid (20 mL) at 140° C. for 4 hours, then cooled to room temperature. The reaction was poured into ice water (400 mL), and the resultant precipitate was collected by filtration to give 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.668 g, 77%) as a light yellow solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ7.42 (m, 2H), 7.79 (m, 1H), 7.96 (d, J=8.4 Hz, 1H), 12.72 (s, 1H). MS 205 (MH+)
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:10]=2[N:9]=[C:8]1[S:33][CH3:34])(=O)C.COCCOC.[OH-].[Na+].Cl>CO>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:16]3[C:10]4[N:9]=[C:8]([S:33][CH3:34])[N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[C:11]=4[CH:14]=[CH:15]3)=[CH:19][CH:20]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1CCO
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of 3-acetoxyethyl-7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (410 mg) in methanol (8 ml)-DME (4 ml) was added 1N-aqueous sodium hydroxide solution (1.64 ml) and the mixture was stirred for 2 hours. This reaction mixture was neutralized with 1N-hydrochloric acid (1.64 ml) and the precipitate was collected by filtration, washed serially with water, methanol and ether, and dried to provide the title compound (295 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O-:18].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:18][CH3:17])=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1cc2nc(N)c(Cl)nc2cc1OC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nc(N)c(OC)nc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To 2-amino-3-chloro-6,7-dimethoxy quinoxaline (3.27 g, 13.6 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (4.41 g, 20.4 mmol) in methanol was added at room temperature and stirred further at room temperature for 2 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 2.73 g of the titled compound (yield, 85%).
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13])([CH3:6])[CH3:5].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13])([CH3:6])[CH3:5])=[N+:18]=[N-:19]
Reactant: CC(C)(C(=O)CBr)c1ccc(F)c(C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(F)c(C#N)c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a stirred solution of 5-(4-bromo-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (10 g, 35.2 mmol) in DMF (100 mL) at 0° C. was added NaN3 (2.52 g, 38.7 mmol, 1.1 eq) portionwise. After stirring 2 h, the residue was diluted with water and extracted with EtOAc. The combined extracts were washed with brine (100 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (silica, Hex/EtOAc=4:1) to give 5-(4-azido-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (6.6 g, 2 step overall yield 78%). 1H NMR (400 MHz, CDCl3) δ 7.57-7.55 (m, 1H), 7.50-7.46 (m, 1H), 7.25 (t, J=7.2 Hz, 1H), 3.8 (s, 2H), 1.55 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+].[C:13](O)(=O)[CH3:14].O>C(#N)C>[CH2:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH3:14]
Reactant: CC(=O)O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCNc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture composed of 4-aminobenzoic acid (30 g), sodium borohydride (32.3 g) and acetic acid (550 cc) is left stirring for 26 hours at 25° C. The reaction mixture is then concentrated to dryness at 70° C. under reduced pressure (4 kPa). The product obtained is treated with distilled water (2000 cc) and the precipitate formed is separated by filtration, washed with distilled water (20 cc) and dried in the air. The product obtained is dissolved in boiling acetonitrile (250 cc). After 2 hours' cooling at 25° C., the crystallized solid is separated by filtration, washed with acetonitrile (10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 4-Ethylaminobenzoic acid (18 g), m.p. 174° C., is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28]Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:28][CH2:27][CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: ClCCCCc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3ccccc3)CC2)c1
Yield: 25.1 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100 mmol), 4-phenyl-1-chlorobutane (21.1 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) was heated at reflux temperature for 3 days. The reaction mixture was concentrated and chromatographed using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] afforded the product, 2-methyl-N-{3-[1-(4-phenylbutyl)-4-piperidinyl]phenyl}propanamide (9.50 mg, 25.1% yield) as a thick oil: 1H NMR δ 7.37 (s, 1H), 7.29 (apparent d, 1H, J=7.9 Hz), 7.18 (m, 3H), 7.11 (m, 3H), 6.90 (apparent d, 1H, J=7.9 Hz), 3.02 (d, 2H, J=6.8 Hz), 2.41 (m, 4H, partially hidden), 2.01 (m, 2H), 1.78 (m, 4H), 1.57 (m, 4H), 1.18 (d, 6H, J=7.7 Hz); ESMS m/e: 379.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([CH:17]=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O-])(O)=[O:34].[Na+].BrBr.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO.O>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([C:17]([O:34][CH3:33])=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:12]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1[C@H](C=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Reactant: O=C([O-])O
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Yield: 107.1 %

Procedure:
To a stirred and ice-cooled mixture of crude (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-formyl-5-methyl-2-phenylpyrrolidine (3.66 g, 5.90 mmol) and NaHCO3 (19.8 g, 0.24mol) in MeOH--H2O (9:1 by volume; 30 ml) was added a 2.0 M solution of Br2 in MeOH--H2O (9:1; 30 ml, 60 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours, during which the color changed from deep red to orange. Sat. Na2S2O3 (hypo) aq. solution was added dropwise to the mixture with ice-cooling, until the orange color due to the excess Br2 was discharged. The mixture was filtered through a pad of Celite, and the filter cake was washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo. The syrupy residue was diluted with AcOEt--PhMe (2:1, 120 ml), washed with sat. Na2S2O3 aq. solution (×2), sat. NaHCO3 aq. solution (×1), and sat. NaCl aq. solution, dried (MgSO4), and concentrated in vacuo to give a white solid (2.96 g). This was recrystallized from AcOEt-n-hexane to give title compound (2.44 g, 88% in 2 steps from (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-hydroxymethyl-5-methyl-2-phenylpyrrolidine) as white powders. mp 147-148 C.; IRmax (nujol): 3310(s), 1728(s), 1701(s, shoulder), 1690(vs), 1537(s), 1535(s), 1280(m), 1165(m), 750(m), 700(s) cm-1 ; 1H-NMR δ: 7.52-7.15(m, 9H), 7.05(br.s, 1H), 5.28(br.d, J=8.1 Hz, 1H), 5.05(br.s, 2H), 4.60(ddd, J=11.7, 8.8, 8.1 Hz, 1H), 4.35-4.17(m, 1H), 4.02(br.d, J=8.8 Hz, 1H), 3.71(s, 3H), 2.58(dd, J=11.7, 9.9 Hz, 1H), 1.62(br.d, J=5.5 Hz, 3H), 1.39(s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]2>>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]3)[C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2[nH]c(=O)ccc12

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 137 mg of 5-amino-8-fluoroquinolin-2(1H)-one. The title compound is obtained analogously to Example 3 by reaction of the imine that is formed with 1.4 ml of titanium tetrachloride solution (1 M in dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[Si:19]([C:26]1[O:27][C:28]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=2[C:30]=1[CH:31]=[O:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.C1(C)C=CC=CC=1>[Si:19]([C:26]1[O:27][C:28]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=2[C:30]=1[C:31](=[O:32])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: COc1cc(I)cc(OC)c1OC
Reactant: COc1ccc2c(C=O)c([Si](C)(C)C(C)(C)C)oc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 3,4,5-trimethoxyiodobenzene (377 mg, 1.27 mmol) in dry tetrahydrofuran (1 mL) at −78° C. under nitrogen was added n-butyllithium (795 μL, 1.59 mmol, 2M solution in cyclohexane) and the reaction mixture was stirred at this temperature for 40 minutes. After this time a solution of 2-t-butyldimethylsilyl-3-formyl-6-methoxybenzofuran (310 mg, 1.07 mmol) in dry tetrahydrofuran (1 mL) was added to the reaction dropwise via syringe pipette. The reaction mixture was stirred at −60° C. for 20 minutes and then allowed to warm to 0° C., stirred for 10 minutes, quenched with saturated ammonium chloride solution (2 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water (10 mL), dried over magnesium sulfate and the solvent was removed under vacuum to give a residue that was co-distilled with toluene. The crude product (908 mg) was dissolved in dry tetrahydrofuran (10 mL) and treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (900 mg, 1.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours (monitored by tlc) and then loaded onto silica (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine, 90:9:1) to afford the title compound as a light yellow paste that crystallised on standing (232 mg, 48%); 1H NMR (300 MHz, CDCl3) δ 7.14 (s, 2H, benzoyl Hs), 7.05 (d, 1H, J=2.45 Hz), 6.77 (dd, 1H, J=8.76, 2.17 Hz), 6.56 (d, 1H, J=8.38 Hz), 3.94 (s, 3H, OMe), 3.85 (s, 6H, 2×OMe), 3.78 (s, 3H, OMe), 1.00 (s, 9H), 0.28 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 190.51 (CO), 164.77, 158.23, 158.12, 152.64, 142.35, 133.19, 131.37, 123.19, 121.04, 119.63, 112.26, 107.03, 104.96, 95.00, 60.47, 55.81, 55.60, 55.13, 26.43, 17.29, −6.09.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3][CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:28][C:24]1[N:25]=[C:26]([O:8][CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[Cl:9])(=[O:19])=[O:18])=[N:22][CH:23]=1
Reactant: OCc1cncnc1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cncnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyrimidine-5-methanol (0.035 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.07 g). Yield 0.015 g.