Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].CCOC(/N=N/C(OCC)=O)=O.O[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CN(C=O)C.CCOCC>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][O:1][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
A solution of N-(2-hydroxyethyl)phthalimide (Aldrich, 19-1, 6.36 g, 33 mmol) and DEAD (5.7 mL, 36 mmol) in 25 mL THF and 10 mL DMF was added to a solution of methyl 4-hydroxybenzoate (1-2, 5.00 g, 33 mmol) and Ph3P (9.53 g, 36 mmol) in 100 mL THF during 1 h. After an additional hour the reaction was diluted with ether, washed twice with water, then 1N NaOH and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica gel, CH2Cl2) provided 19-2 as a white solid.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].CN(C=O)C.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([OH:30])[C:28]=1[I:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:30][CH:2]([CH3:4])[CH3:3])[C:28]=1[I:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)I
Reactant: CCOC(=O)c1cc(O)c(I)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccccc2)c(I)c(OC(C)C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Iodopropane (1.47 mL) was added to a DMF (30 mL) suspension of ethyl 3-(benzyloxy)-5-hydroxy-4-iodobenzoate (2.94 g) and potassium carbonate (1.53 g), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.72 g).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[I:11][CH3:12]>C1C=CC=CC=1>[I-:11].[CH3:10][O:9][C:1]([C:2]1[CH:7]=[CH:6][N+:5]([CH3:12])=[CH:4][CH:3]=1)=[O:8]
Reactant: CI
Reactant: COC(=O)c1ccncc1
Solvent: c1ccccc1
Product: COC(=O)c1cc[n+](C)cc1
Product: [I-]
Temperature: 110 °C
Yield: 45.8 %

Procedure:
To a solution of methyl isonicotinate (5.0 g, 36 mmol) in benzene (165 mL) is added iodomethane (4.5 mL, 72 mmol). The mixture is heated in a 110° C. oil bath for two hours and then allowed to cool to room temperature. The solid is collected by Büchner filtration, washed with hexanes and diethyl ether, and dried under house vacuum to give 4-methoxycarbonyl-1-methylpyridinium iodide (4.6 g, 46%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:26][CH2:27][CH3:28])(OCC)(OCC)[CH2:18][CH3:19].C(O[C:33](=[O:35])[CH3:34])(=O)C>>[C:33]([N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=2)[C:11](=[C:17]([O:26][CH2:27][CH3:28])[C:18]2[CH:19]=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:12]1=[O:16])(=[O:35])[CH3:34]
Reactant: CCOC(CC)(OCC)OCC
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1

Procedure:
Prepared from 6-phenyl-2-indolinone, triethyl orthopropionate and acetic anhydride
Reaction SMILES: CN(C)C=O.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Cl[CH2:20][N:21]([N:23]1[C:32]2[C:27](=[CH:28][C:29]([F:35])=[C:30]([F:34])[C:31]=2[F:33])[C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24]1)[CH3:22]>O.C(OCC)(=O)C>[F:35][C:29]1[CH:28]=[C:27]2[C:32](=[C:31]([F:33])[C:30]=1[F:34])[N:23]([N:21]([CH3:20])[CH2:22][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH:24]=[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]2=[O:36]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)c1cn(N(C)CCl)c2c(F)c(F)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(N(C)CC(C(=O)OCC)C(=O)OCC)c2c(F)c(F)c(F)cc2c1=O

Procedure:
To dimethylformamide (1.5 ml) solution of diethyl malonate (47.8 μl), was added sodium hydride (24.4 mg) with stirring under ice-cooling, and the mixture was stirred for 20 minutes with ice-cooling. To the solution was added ethyl 1-[N-(chloromethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (100 mg) with stirring under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The reaction solution was added to a mixed solution comprising ethyl acetate (30 ml) and water (30 ml) for extraction. The organic layer was washed with water (30 ml×3) and a saturated brine(30 ml×3), dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to column chromatography with silica gel (3 g), eluted with a mixed solvent of dichloromethane ethyl acetate (20/1 to 10/1) and concentrated to dryness under reduced pressure to obtain ethyl 6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(ethoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate (49.1 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH3:27])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)=[C:19]([O:26][CH3:27])[CH:18]=1
Reactant: Cn1ccnc1CNc1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ccncc1NCc1nccn1C

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-((1-methyl-1H-imidazol-2-yl)methyl)pyridin-3-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 18 hours at 90° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of CH2Cl2:MeOH (100:0 to 85:15). Light yellow solid (95%). MS (ESI): m/z=313.145 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>CC(N(C)C)=O>[N:21]1([C:2]2[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Reactant: C1CNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16), in DMA is treated with a large excess of azetidine (e.g., ˜30 eq). The resultant solution is warmed to about 100° C. and stirred at that temperature for about 18 h. The reaction solution is cooled to room temperature, poured into 1N NaOH solution and then extracted with EtOAc. The organic phases are dried, e.g., over MgSO4 or Na2SO4, filtered and concentrated. The crude product is purified using SiO2 chromatography and an appropriate gradient (MeOH—CH3CN (1:7)/CH2Cl2) to yield 2-(5-(azetidin-1-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-23) as a solid.
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][O:14][C:13]1=[O:24])=[O:11])(=O)OCC)C.[Cl-].[Li+].N12CCCN=C1CCC[CH2:29][CH2:28]2.[C:38]([O:42][C:43]([N:45]1[C:49](CC=O)([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:48][O:47][C:46]1([CH3:61])[CH3:60])=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(#N)C.C(OCC)C>[C:38]([O:42][C:43]([N:45]1[CH:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:48]([CH2:28][CH:29]=[CH:9][C:10]([N:12]2[CH:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][O:14][C:13]2=[O:24])=[O:11])[O:47][C:46]1([CH3:61])[CH3:60])=[O:44])([CH3:39])([CH3:40])[CH3:41]
Reactant: CCOP(=O)(CC(=O)N1C(=O)OCC1Cc1ccccc1)OCC
Reactant: CC(C)(C)OC(=O)N1C(CC=O)(Cc2ccccc2)COC1(C)C
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC=CC(=O)N2C(=O)OCC2Cc2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A solution of [2-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-oxo-ethyl]-phosphonic acid diethyl ester (36.72 g) in dry acetonitrile (550 ml) was stirred at room temperature under nitrogen and treated with lithium chloride (4.39 g) followed by the dropwise addition of 1.8-diazabicyclo (5.4.0) undec-7-ene (g, mmol). After 5 minutes, the crude 4-benzyl-2,2-dimethyl-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester dissolved in dry acetonitrile (350 ml) was added via a cannula, and the resulting mixture was stirred at room temperature for 80 minutes. The mixture was then diluted with diethyl ether (1 L) and washed with brine (500 ml). The organic layer was dried (anhydrous magnesium sulfate) and concentrated in vacuo . Purification by flash chromatography on silica gel (ethyl acetate/hexane: 1/4 to 3/7) provided of 4-benzyl-5-[4-(4-benzyl-2-oxo-oxazolidin-3-yl)-4-oxo-but-2-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (29.33 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:34]1C=C(S(Cl)(=O)=O)C=C[CH:39]=1>>[CH2:34]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:16][CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:39]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=469.0 (M−H), was prepared in analogy to example 57, steps 1 to 6. Step 5 was performed using 3-chloro-benzenesulfonyl chloride, yielding 4-{[1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>>[CH3:22][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=2)[CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCI
Product: CCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodopentane and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 97°-99° C.
Reaction SMILES: C([N:3](C=O)[CH2:4][C:5]([C:7]1[CH:11]=[C:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:9]([CH3:21])[CH:8]=1)=[O:6])=O>Cl.CCO>[ClH:19].[NH2:3][CH2:4][C:5]([C:7]1[CH:11]=[C:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:9]([CH3:21])[CH:8]=1)=[O:6]
Reactant: Cn1cc(C(=O)CN(C=O)C=O)cc1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Cn1cc(C(=O)CN)cc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
6.18 g (0.0186 mole) 2-[(Bis-formyl)amino]-1-[5-(4-chlorobenzoyl)-1-methyl-1H -pyrrol-3-yl]-ethanone was stirred 3 days in 5% HCl/EtOH. A 0.5 mL portion of conc. HCL was added and the reaction stirred for two more days. The solid was collected by filtration. The solid was stirred in refluxing methanol and the undissolved solid collected by filtration and discarded. The filtrate was cooled to room temperature and diethyl ether was added. The solid was collected. It was twice treated with boiling methanol to give pure product: mp 290° C. (decomp.); mass spectrum (CH4-Cl) m/z=277 (M+1); NMR (Me2SO-d6) d 8.2 (br s, 4H); 7.85 (d, 2H); 7.6 (d, 2H); 7.2 (s, 1H); 4.3 (s, 2H); 4.0 (s 3H). Anal Calcd for C14H13ClN2O2-HCl: C, 53.69; H, 4.51; N, 8.94. Found: C, 53.91; H, 4.4.1; N, 8.76.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([C:19]1[C:20]([Cl:29])=[N:21][C:22]3[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:6]2.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl.[C:51]([N:58]1[CH2:63][CH2:62][CH:61]([C:64](O)=[O:65])[CH2:60][CH2:59]1)([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>CN(C=O)C>[C:54]([O:53][C:51]([N:58]1[CH2:63][CH2:62][CH:61]([C:64]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:7]([C:19]2[C:20]([Cl:29])=[N:21][C:22]4[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6]3)=[O:65])[CH2:60][CH2:59]1)=[O:52])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CN)ccc21
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc3c(c2)cc(-c2cc4ccccc4nc2Cl)n3C(=O)OC(C)(C)C)CC1

Procedure:
A solution of tert-butyl 5-(aminomethyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-4, 204 mg, 0.5 mmol, 1 equiv), HOAT (68 mg, 0.5 mmol, 1 equiv), triethylamine (101 mg, 1.0 mmol, 2 equiv), EDC (144 mg, 0.75 mmol, 1.5 equiv) and 1-BOC-piperidine-4-carboxylic acid (126 mg, 0.55 mmol, 1.1 equiv) in DMF (5 mL) was stirred under ambient conditions for 18 hr. The reaction was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to provide tert-butyl 5-[({[1-(tert-butoxycarbonyl)-4-piperidinyl]carbonyl}amino)methyl]-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-5) as a white foam. 1H NMR (400 MHz, CDCl3) δ8.25 (d, 1H, J=8 Hz), 8.16 (s, 1H), 8.05 (d, 1H, J=8 Hz), 7.85 (d, 1H, J=8 Hz), 7.76 (t, 1H, J=8 Hz), 7.59 (t, 1H, J=8 Hz), 7.49 (s, 1H), 7.28 (dd, 1H, J=8, 2 Hz), 6.61 (s, 1H), 4.48 (d, 2H, J=5 Hz), 4.12 (m, 2H), 2.72 (m, 2H), 2.26 (m, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.42 (s, 9H), 1.25 (s, 9H).
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+].O1[C:23]2=[CH:24][CH:25]=[CH:26][C:27]([NH2:28])=[C:22]2C=C1.Cl.[CH3:30]N(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:30][N:10]1[C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=[C:9]1[CH2:14][C:15]([NH:28][C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17]
Reactant: Nc1cccc2occc12
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccccc2)nc(N2CCOCC2)cc1=O
Yield: 87.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 178 mg of 1-benzofuran-4-amine, and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 3 ml of N,N-dimethylformamide. 275 mg of 2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.[C:13]1([C@@H:19]([N@:21]2[CH2:23][CH:22]2[CH:24]=[O:25])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[C:2]1([C@H:24]([CH:22]2[CH2:23][N@@:21]2[C@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:20])[OH:25])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccccc1)[N@]1CC1C=O
Reactant: Brc1ccccc1
Agent: C[C@@H](c1ccccc1)[N@@]1CC1[C@H](O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)[N@]1CC1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of bromobenzene (4.93 g, 31.4 mmol) in THF 125 mL under nitrogen at −78° was added t-BuLi (1.7 M in pentane, 50 mL). The mixture was stirred for 0.5 h at room temperature. The mixture was cooled down to −78° C. and a solution of (R)-1-((S)-1-phenylethyl)aziridine-2-carbaldehyde EBE 06048 (2.5 g, 14.3 mmol) in THF (16.7 mL) at −78° C. was added dropwise. The reaction mixture was treated with H2O (20 mL), the organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a residue that was purified by column chromatography using a gradient of 0-20% [v/v] EtOAc in cyclohexane to give (R)-phenyl((R)-1-((S)-1-phenylethyl)aziridin-2-yl)methanol EBE 06066 (3.13 g, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[Br:13]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(#N)C>[Br:13][C:6]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:5]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: COc1cc([N+](=O)[O-])cc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A clear yellow solution of 2-methoxy-4-nitroaniline (10 g, 15 59.5 mmol) in acetonitrile (300 mL) at room temperature was treated with N-bromosuccinimide (10.58 g, 59.5 mmol). The reaction was protected from light and stirred for 2 hours at room temperature. TLC (3:1 hexane:ethyl acetate) analysis showed starting material (Rf 0.14) replaced with a higher spot (Rf 0.23). The reaction was concentrated in vacuo, treated with carbon tetrachloride, filtered through celite and concentrated in vacuo to give 2-bromo-6-methoxy-4-nitroaniline as a yellow brown solid. 1H NMR (δ, CDCl3): 8.11 (1H, d, J=2.2 Hz), 7.63 (1H, d, J=2.2 Hz), 4.96 (2H, br s), 3.96 (3H, s); MS (m/z) 249, 247.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Yield: 74.5 %

Procedure:
50 gm of succinic anhydride and 133.3 gm of aluminum chloride was added to 79.6 gm of fluorobenzene, and the mixture was heated under reflux for 6 hours. After evaporating the surplus fluorobenzene, the residue was added to 2 l of 1% hydrochloric acid aqueous solution. The precipitate was collected by filtration, washed with water, and dried to obtain 73 gm of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1OCCOCCOCCOCCOCCOC1.[CH:37]1(Br)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CS(C)=O.O>[CH:37]1([O:7][N:8]2[C:9](=[O:18])[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:13])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: BrC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
Solid potassium carbonate (6.91 g, 50.0 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) and 18-crown-6 (661 mg, 2.5 mmol) in dimethyl sulfoxide (62 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture cyclohexyl bromide (12.3 mL, 100.0 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-cyclohexyloxy-isoindole-1,3-dione (5.67 g, 93%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3([CH2:28]OS(C)(=O)=O)[CH2:27][CH2:26]3)[O:16][N:15]=2)=[CH:10][CH:9]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:17]([C:25]3([CH2:28][S:2][CH3:1])[CH2:26][CH2:27]3)[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: COCOc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2noc(C3(CSC)CC3)c2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a mixture consisting of sodium thiomethoxide (0.33 g) in N,N-dimethylformamide (3 mL) is added a mixture consisting of methanesulfonic acid 1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl ester (synthetic intermediate prepared in Example 11, Step iv, 1 g) in N,N-dimethylformamide at 0° C. The mixture is stirred at 80° C. for four hours and is cooled to room temperature. The mixture is then diluted with ethyl acetate (50 mL) and is sequentially washed with 1 N hydrochloric acid solution (3×15 mL), water (15 mL), and brine solution (15 mL.) The mixture is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate 3-(4-methoxymethoxy-phenyl)-5-(1-methylsulfanylmethyl-cyclopropyl)-4-phenyl-isoxazole (0.89 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][CH:19]3O)=[CH:12][CH:13]=1)=[O:6].C1C=C[NH+]=CC=1.Br[Br-]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH:18]=[CH:19]3)=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3O)nc1)c1ccc(Cl)c(Cl)c1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2cccc3c2CC=C3)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
1.50 g of 3,4-dichloro-N1-[6-(1-hydroxy-2,3-dihydro-1H-inden-4-yloxy)-3-pyridinyl]benzamide obtained in Example 34 was dissolved in 15 ml of acetic acid, and 1.16 g of pyridinium bromide perbromide was added to the resulting reaction solution and the mixture was stirred at 80° C. After 4 hours, the reaction solution was poured into iced water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane (1:3)) to obtain 430 mg of the titled compound.