Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1I
Reactant: Clc1ccc2cc[nH]c2c1
Product: Fc1ccccc1-n1ccc2ccc(Cl)cc21

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-fluoro-2-iodobenzene: ESMS m/e: 245.9 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1([CH3:34])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=O)[OH:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15]>C(Cl)Cl>[CH3:5][C:6]1([CH3:34])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=[O:12])[Cl:3])[C@H:7]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Reaction time: 1.75 h

Procedure:
10 ml of thionyl chloride were added all at once at 20° C. to a solution of 4.5 g of the product of Step C in 20 ml of methylene chloride and the mixture was stirred for 105 minutes and was evaporated to dryness under reduced pressure to obtain 4.7 g of (S)α-cyano-3-phenoxy-4-fluorobenzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-chloro-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[O:2].C(O)(=[O:15])C>>[CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:15])[CH2:6][CH2:5]1)=[O:2]
Reactant: O=CNC1CCCc2sccc21
Reactant: CC(=O)O
Product: O=CNC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 22.4 g of ceric sulfate in 50% aqueous acetic acid is stirred overnight at room temperature and 2 g of N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is added. After 6 hours, the mixture is filtered, and the filter cake is washed with 50% aqueous acetic acid. The work-up procedure of Example 1 is then followed with the filtrate to give 1.1 g of the title compound, m.p. 102 to 114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2cccc(C(F)(F)F)c2)cc1
Yield: 53.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3-trifluoromethyl-benzyl bromide (145 mg, 0.6 mmol) to afford the title product (120 mg, 55% yield); LCMS; 100% APCI+, Calcd: 451.49. Found m/z: 452.27 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.26-3.44 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 5.05 (s, 2H), 6.88 (s, 4H), 7.49 (t, J=7.6 Hz, 1H), 7.57-7.62 (m, 2H), 7.70 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH2:10][CH3:11])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.P(Br)(Br)([Br:24])=O>C(OCC)(=O)C>[Br:24][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH2:10][CH3:11]
Reactant: CCC(O)c1cnc(Cl)nc1Cl
Reactant: O=P(Br)(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC(Br)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (±)-1-(2,4-dichloro-pyrimidin-5-yl)-propan-1-ol (0.26 g; 1.26 mmol) (from Example 7a supra) in diisopropylethylamine (0.55 mL; 3.13 mmol) (Aldrich) was cooled slightly (18° C.) to help offset the exothermicity of the reaction. Neat phosphorus oxybromide (0.35 g; 1.36 mmol) (Aldrich) was added in one portion. The cooling bath was removed and reaction mixture stirred at room temperature. After 15 minutes, the reaction mixture was diluted with ice and ethyl acetate. The organic phase was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 12M; 5:95 ethyl acetate-hexanes) gave crude (±)-5-(1-bromopropyl)-2,4-dichloro-pyrimidine which was used in subsequent steps without further purification. (Yield 0.23 g). The material showed 3 peaks for the pyrimidine ring proton in its NMR spectrum indicating some displacement of the ring chlorines with bromine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[N:1]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: F[n+]1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=Nc1ccccn1
Temperature: -78 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
Sodium azide (390 mg) was dissolved in 30 ml of methanol and cooled at −78° C., 6.0 ml of a methanolic solution of 740 mg of 1-fluoropyridinium triflate was dropped thereinto and the mixture was stirred for 4 hours. The solvent was evaporated in vacuo and the residue washed with 50 ml of diethyl ether to give 296 mg of the title compound in an ark oily crude product.
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[C:29]([OH:31])=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:59]([N:66]([CH3:71])[CH2:67][CH2:68][NH:69][CH3:70])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([N:66]([CH2:67][CH2:68][N:69]([CH3:70])[C:29]([C@@H:11]1[CH2:12][N:13]([C:16](=[O:28])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][N:10]1[C:8](=[O:9])[N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:31])[CH3:71])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CNCCN(C)Cc1ccccc1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)N(C)CCN(C)Cc2ccccc2)C1
Yield: 77.6 %

Procedure:
According to the procedure of Example 1, Step E above, 48 mg (0.094 sole) of 1-(N,N-diphenylcarbamoyl)-4-(N,N-di-n-pentylcarbamoyl)piperazine-2carboxylic acid, 14 mg (0.104 mmole) of HOBt, 25 mg (0.132 mmole) of EDAC, and 34 mg (0.19 mmole) of N-benzyl-N-methyl-N'-methylethylenediamine after purification by flash chromatography on 16 g of silica gel eluting with 400 mL of 100:4 CH2Cl2 :MeOH provided 49 mg (78%) of an oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10]([O:12]CC)=O>CCOCC>[C:1]1([NH:8][C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cccc(N)c1
Solvent: CCOCC
Product: CCOC(=O)C(=O)Nc1cccc(NC(=O)C(=O)OCC)c1

Procedure:
A mixture of m-phenylenediamine (10.8 grams) 0.10 ml.) and diethyl oxalate (50 ml.) is refluxed for 2.5 hours. The cooled reaction mixture is diluted with ether (200 ml.) and the crude product collected (19.2 grams, M.P. 150° C.). Two recrystallizations from methanol give off white crystals (6.65 grams, 155°-160°).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC#N.Cl[CH2:27][C:28]([N:30]1[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH2:27][C:28]([N:30]3[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]3)=[O:29])[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC1CN(C(=O)CCl)C1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC1CN(C(=O)CN2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine and MeCN was added to 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg) and potassium carbonate (219 mg), followed by stirring at 80° C. for 3 hours. CHCl3 was added to the reaction mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 2-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}-1-(3-met hoxyazetidin-1-yl)ethanone (354 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:23]=[O:24])=[CH:11][N:10]=1)([CH3:3])[CH3:2].[Se](=O)=[O:29]>C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:23]=[O:24])=[CH:11][N:10]=1)=[O:29])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: COc1cc2c(C=O)cnc(Cc3cccc(OC(C)C)c3)c2cc1OC
Solvent: CCOC(C)=O
Product: COc1cc2c(C=O)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Yield: 77.1 %

Procedure:
A solution of 1-(3-isopropoxy-benzyl)-6,7-dimethoxy-isoquinoline-4-carbaldehyde (200 mg, 0.547 mmol) and selenium dioxide (121 mg, 1.09 mmol) in ethyl acetate was refluxed for 45 min. The mixture was cooled and filtered through celite. The celite was washed well with ethyl acetate and the combined filtrates were concentrated in vacuo to afford 1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carbaldehyde (160 mg, 77%) as a light yellow solid that was used without further purification: APCI-MS (M+H+) m/e 380; 1H NMR (300 MHz) compatible.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].C([NH+](CC)CC)C>CN1CCCC1=O.O>[O:17]=[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:20][N:19]=[N:18][N:2]=2)=[CH:8][N:7]=1)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCC(=O)Nc1ccc(C#N)cn1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CCC(=O)Nc1ccc(-c2nnn[nH]2)cn1
Yield: 25 %

Procedure:
A mixture of methyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A1 (0.200 g, 0.857 mmol), sodium azide (0.169 g, 0.09 ml, 2.57 mmol) and triethylammonium chloride (0.187 g, 0.17 ml, 1.33 mmol) was stirred 4 h at 150° C. in 1-methyl-2-pyrrolidinone (10 mL). The mixture was cooled down and diluted with water. After acidification with aqueous hydrochloric acid (1N), the filtrate was extracted twice with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate and filtered to give methyl 4-oxo-4-[[5-(1H-tetrazol-5-yl)-2-pyridyl]amino]butanoate A65 (0.06 g, 25% yield). M.p.: 246-248° C., LC-MS (Method F) RT 0.53, 277 (M+H+).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([C:12]([O:11][CH3:10])=[O:22])=[CH:14][CH:15]=2)=[O:18])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a 3-necked round-bottomed flask equipped with a magnetic stir bar were added anisole (31 mL, 30.8 g, 0.285 moL) and terephthalic acid monomethyl ester chloride (19.6 g, 0.099 moL). The flask was equipped with a powder addition funnel and nitrogen inlet. The powder addition funnel was charged with AlCl3 (40.2 g, 0.301 moL). The reaction mixture was cooled in an ice-water bath and the AlCl3 was added slowly, portionwise with stirring, under a nitrogen atmosphere. The ice-water bath was removed and the stirred reaction mixture was allowed to warm to room temperature for 3.5 h. The viscous reaction mixture was cooled in an ice-water bath and ice was added very slowly portionwise (Note: significant HCl was released upon addition of ice) followed by the slow addition of ice-water. The reaction mixture solidified upon quenching. The solid was filtered, washed with water, and allowed to stand overnight at RT. The solid was washed with water and triturated with hexanes (2×) to give a pink solid. The crude product was recrystallized from EtOAc to give a white solid. The solid was dried to give 16.0 g (60%) of compound 23 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 3.84 (s, 3H), 3.88 (s, 3H), 7.08 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[C:43]([O:51][C:52]([F:55])([F:54])[F:53])[CH:42]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:47]([C:44]1[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][C:43]=1[O:51][C:52]([F:53])([F:54])[F:55])(=[O:49])=[O:48])[C:6](=[O:11])[C:5]2([N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(C)cc1C1(N2CCN(C(=O)OC(C)(C)C)CC2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3CCN(C(=O)OC(C)(C)C)CC3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 80.5 %

Procedure:
With 1.70 g of the compound obtained in Step 109-5 and 1.00 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 2.01 g of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14]>N([O-])=O.[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)ccc1O
Temperature: 15 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
In a 500-ml flask, place 44.8 g (0.4 m) of 4-fluorophenol (1a; X=F) and 132 ml of acetic acid and stir to a solution. Add 0.6 g of sodium nitrite and cool the solution to 15° C. Add 36.0 g (0.4 m) of 70% nitric acid in drop wise keeping the temperature at 22-27° C. over 10-15 min. Stir the resulting yellow slurry at room temperature for 3 hrs. Warm the mixture to 65° C. to make a clear solution and add 132 ml of warm (65° C.) water slowly. Stir the resulting slurry and cool to 15° C. Collect solid, wash with water thoroughly, and dry in air to give 53.4 g (85%) of 4-fluoro-2-nitrophenol (2a; X=F) as yellow granular solids.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:17][CH2:18][N:19]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:20][CH2:21]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=c1[nH]nc2c(N3CCNCC3)nc3ccc(F)cc3n12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: N#Cc1ccc(N2CCN(c3nc4ccc(F)cc4n4c(=O)[nH]nc34)CC2)nc1
Temperature: 25 °C

Procedure:
A solution of 40 mg of 8-fluoro-4-piperazin-1-yl-[1,2,4]triazolo[4,3-a]quinoxalin-1-one, 36.8 mg of 2-chloro-5-cyanopyridine, and 47 mg of sodium carbonate in n-butanol (1 mL) was heated to reflux for 24 hrs. The reaction mixture was cooled to room temperature, filtered through a plug of diatomaceous earth, and evaporated to dryness. The residue was separated by silica gel chromatography to provide a white solid. MS (M−H)−=389.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C(O)C.O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[O:15])=[CH:20][CH:19]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Solvent: O
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1)c1c(O)c2ncccc2[nH]c1=O
Temperature: 100 °C

Procedure:
A mixture of methyl 4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.2 g, 0.91 mmol) and 4-fluorobenzyl amine (Aldrich, 0.31 mL, 2.72 mmol) in absolute ethanol (5 mL) was heated to 100° C. for 6 hours. A thick paste formed. The reaction was diluted with water and the solids collected. The crude material was purified by preparative reverse phase HPLC eluting with a gradient of 5-95% acetonitrile/water (0.1% TFA). The product precipitated from the column fractions was collected to afford the desired product as a white solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:38][CH:39]=[CH2:40]>O>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:40][CH:39]=[CH2:38])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCBr
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: C=CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt and 75 parts of hexamethylphosphoric triamide is stirred and heated to 110° C. for a while. After cooling to 20° C., 3.63 parts of 3-bromo-1-propene are added dropwise. Upon completion, stirring is continued for 20 hours at room temperature. The reaction mixture is poured onto 150 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from hexane, yielding 2-propenyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 57.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:22]=[N:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CO>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([C:8]1[CH2:22][N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: C=NCCN1CCOCC1
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(Cl)c(Cl)c2)O1
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (66 mg, 0.2 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.5 mL, 0.3 mmol) was heated at 70° C. for 1.5 h. The reaction mixture was then cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as eluent. The fractions containing the product were combined and concentrated to give a white powder (23.3 mg, 22% yield). 1H NMR (500 MHz, DMSO) δ: 9.50 (1H, br s), 8.08 (1H, t, J=6.2 Hz), 7.59 (1H, d, J=8.2 Hz), 7.53 (1H, d, J=1.8 Hz), 7.28 (1H, dd, J=8.2, 1.8 Hz), 4.42 (2H, d, J=6.1 Hz), 4.04 (2H, s), 4.02–3.95 (2H, m), 3.81–3.77 (2H, m), 3.73–3.37 (6H, m), 3.15–3.06 (2H, m). HRMS calcd for C18H22Cl2N3O4 (M+H): 414.09875. found: 414.0987.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>>[CH3:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][CH:25]=1)[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.12 g, 10%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 4-methylphthalic anhydride (0.56 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(OCC[CH:6]([C:29]([OH:31])=[O:30])[N:7]([C:19](OCC1C=CC=CC=1)=O)[CH2:8][P:9]([S:15][CH2:16][CH:17]=[CH2:18])([S:11][CH2:12][CH:13]=[CH2:14])=[O:10])C.Br.[CH3:33][CH2:34][O:35][CH2:36]C>C(O)(=O)C>[CH2:34]([O:35][CH2:36][CH2:19][N:7]([CH2:8][P:9]([S:11][CH2:12][CH:13]=[CH2:14])([S:15][CH2:16][CH:17]=[CH2:18])=[O:10])[CH2:6][C:29]([OH:31])=[O:30])[CH3:33]
Reactant: CCOCC
Reactant: C=CCSP(=O)(CN(C(=O)OCc1ccccc1)C(CCOCC)C(=O)O)SCC=C
Agent: Br
Solvent: CC(=O)O
Product: C=CCSP(=O)(CN(CCOCC)CC(=O)O)SCC=C

Procedure:
Ethoxyethyl N-carbobenzoxy-N-[bis(allylthio)phosphinylmethyl]glycine (4.8 g., 0.01 mole) was reacted with 32% hydrogen bromide (15 ml) in glacial acetic acid at 0° C. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. Concentration of the solution in vacuo yielded ethoxyethyl N-[bis(allylthio)phosphinylmethyl]glycine as an oil, ND22 =1.5163.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=O)=[CH:18][CH:19]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(C)nc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(C=Cc2ccc(OC)cc2)nc1

Procedure:
The starting material was prepared by refluxing for 72 hours a mixture of methyl 6-methylnicotinate (60.4 g.), anisaldehyde (163.3 g.), acetic anhydride (120 ml.) and xylene (320 ml.). Steam distillation was used to remove the excess anisaldehyde, the acetic acid formed during the reaction and xylene. The residue was dried in the cold, washed with ether, and dried at 60° C. for 12 hours to give methyl 6-p-methoxystyrylnicotinate, m.p. 170° C.