Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[O:6]1[CH2:9][C:8](=[CH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1>>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:8]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][O:6][CH2:9]1
Reactant: C#CCNC
Reactant: O=C(C=C1COC1)OCc1ccccc1
Product: C#CCN(C)C1(CC(=O)OCc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-methyl-propargylamine (0.27 g) and benzyl 2-(oxetan-3-ylidene)acetate (0.41 g) was stirred neat at RT for 12 h. The excess amine was removed by evaporation to give benzyl 2-(3-(methyl(prop-2-ynyl)amino)oxetan-3-yl)acetate quantitatively (0.54 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1[Br:11])=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH2:16]([O:15][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([Br:11])[N:9]([CH:12]([CH3:14])[CH3:13])[N:8]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)nn(C(C)C)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)n1nc(OCc2ccccc2)c(C(=O)O)c1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid ethyl ester (7.7 g) was suspended into 1,4-dioxan (19 mL), and 20% sodium hydroxide aqueous solution (19 mL) was added to the suspension. The mixture was stirred at 100° C. for 8 hours. After the mixture was cooled, the reaction mixture was poured into 2 mol/L hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.6 g).
Reaction SMILES: [Br:1]C(Br)(Br)Br.[CH3:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].C(Br)(Br)Br>O1CCCC1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:7]([CH3:6])([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: BrC(Br)(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: BrC(Br)Br
Solvent: O
Product: COC(=O)C(C)(Br)C(=O)OC
Yield: 87.5 %

Procedure:
A solution of 3.25 g tetrabromomethane (10 mmol), 1.46 g dimethyl methylmalonate (10 mmol), and 100 mg tetra-n-butylammonium fluoride trihydrate (0.316 mmol) in 5 mL tetrahydrofuran (THF) was stirred for 10 min at 24° C. Gas chromatographic analysis of the resulting mixture showed that it contained 87% yield of both dimethyl α-bromo-α-methylmalonate (1.97 g) and bromoform (2.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)C(C)Cc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Cc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step E was prepared from 2-methyl-3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl-}-propionic acid methyl ester of Step δ and benzenesulfonyl chloride, following the method descirbed in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine and with a reaction time of 4 h. 1H NMR (400 MHz, CDCl3) δ 7.87 (m, 3H), 7.69 (m, 1H), 7.61 (m, 1H), 7.54 (m, 4H), 7.10 (m, 3H), 6.98 (d, 1H), 6.85 (d, 1H), 6.75 (s, 1H), 6.44 (m, 1H), 4.31 (s, 2H), 4.29 (s, 2H), 3.61 (s, 3H), 2.87 (dd, 1H), 2.61-2.47 (m, 2H), 1.06 (d, 3H); MS 504 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[C:19]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])=[N:20][O:21][C:22]=3[CH:23]3[CH2:25][CH2:24]3)=[CH:12][C:11]=2[CH3:34])=[CH:8][CH:9]=1)=[O:4].[OH-].[Li+]>CO.C1COCC1.O.Cl>[CH:23]1([C:22]2[O:21][N:20]=[C:19]([C:26]3[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=3[Cl:32])[C:18]=2[CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)=[C:11]([CH3:34])[CH:12]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(-c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1-c1ccc(C(=O)O)s1
Temperature: 55 °C

Procedure:
To a solution of 5-(4-(5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy)-2-methyl-phenyl)-thiophene-2-carboxylic acid methyl ester (0.138 g, 0.27 mmol) in 3 mL of methanol and 3 mL of THF is added a solution of lithium hydroxide (0.06 g, 2.7 mmol) in 3 mL of water. The reaction is heated to 55° C. for 1 hour. The solvent is evaporated to give a white solid. The solid is dissolved in aqueous 1M HCl and is extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. The reaction is filtered and concentrated under reduced pressure to yield the title compound. ES/MS m/e 500.0; 498.1 (M+1).
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24](Cl)(=[O:28])[C:25]([Cl:27])=[O:26]>>[C:25]([Cl:27])(=[O:26])[C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)C(=O)Cl
Yield: 92.5 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step docosanol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce docosyl chlorooxalate having an assay of 91.4% and in a corrected yield of 92.5%. In the second step docosyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product:
Reaction SMILES: [ClH:1].O=[C:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C([BH3-])#N.[Na+]>CO>[ClH:1].[ClH:1].[CH:24]([NH:27][CH:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12)([CH3:26])[CH3:25]
Reactant: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)=O)=C21
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)NC(C)C)=C21

Procedure:
The solution of 0.84 g of 1-(2-oxopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepine hydrochloride, 1.28 ml of isopropylamine, 0.66 ml of 4.4 N methanolic hydrochloric acid and 0.17 g of sodium cyanoborohydride in 13 ml of methanol is refluxed overnight. Additional 0.085 g of sodium cyanoborohydride are added and the whole is again refluxed for 5 hours. The mixture is cooled, acidified to pH=1 with concentrated hydrochloric acid and the methanol evaporated. The aqueous solution is washed with diethyl ether, rendered basic to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The ether extract is evaporated, the residue dissolved in acetone and 0.4 ml of 8 N ethanolic hydrochloric acid are added, to yield the 1-(2-isopropylaminopropyl)-9-methoxy-3-methyl-3,4,5,5 a,6,7-hexahydro-2H-naphth[1,2-d]azepine dihydrochloride melting at 257°-260° with decomposition.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)[CH3:12].C(N(CC)CC)C.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C(O)C>[CH3:28][N:29]1[CH2:34][CH2:33][C:32]2[N:8]([CH2:17][CH2:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:19])[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:31]=2[CH2:30]1
Reactant: CCOC(=O)CCCCl
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCn1c2c(c3cc(C)ccc31)CN(C)CC2
Yield: 11.2 %

Procedure:
Preparation of the title compound was carried out according to General Method 1 by using p-Tolylhydrazine hydrochloride (600 mg, 3.7 mmol), ethyl-4-chlorobutyrate (0.54 ml, 3.7 mmol), triethylamine (1.5 ml, 11.3 mmol) and N-methyl-4-piperidone hydrochloride (0.563 g, 3.7 mmol) in ethanol (10 ml) to obtain 130 mg of ethyl 4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)butanoate after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: N([O:3][C:4](C)(C)[CH3:5])=O.ON1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17]C=C2C1=O.C1(=NO)CCCC1.[N+](C1CCCC1)([O-])=O.C1(=O)CCCC1>C(O)(=O)C.C1CCCC1>[C:4]([O:14][CH:13]1[CH2:12][CH2:15][CH2:16][CH2:17]1)(=[O:3])[CH3:5]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)ON=O
Agent: O=[N+]([O-])C1CCCC1
Agent: ON=C1CCCC1
Solvent: O=C1CCCC1
Solvent: C1CCCC1
Solvent: CC(=O)O
Product: CC(=O)OC1CCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclopentane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclopentanone oxime, nitrocyclopentane, cyclopentanone, and cyclopentyl acetate were formed in yields of 4%, 2%, 3%, and less than 1%, respectively.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:30](=[O:43])[C:29]2=[O:44].[CH3:45][O:46][C:47]1[N:52]=[C:51]([C:53](=[O:55])[CH3:54])[CH:50]=[CH:49][CH:48]=1>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:30](=[O:43])[C:29]2([OH:44])[CH2:54][C:53]([C:51]1[CH:50]=[CH:49][CH:48]=[C:47]([O:46][CH3:45])[N:52]=1)=[O:55]
Reactant: O=C1C(=O)N(CCN2CCCCC2)c2ccc(Cl)cc21
Reactant: COc1cccc(C(C)=O)n1
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: COc1cccc(C(=O)CC2(O)C(=O)N(CCN3CCCCC3)c3ccc(Cl)cc32)n1

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-(2-(piperidin-1-yl)ethyl)indoline-2,3-dione and 1-(6-methoxypyridin-2-yl)ethanone (commercially available from Fisher Scientific). 1H-NMR δ 7.72 (t, 1H), 7.63 (d, 1H), 7.34 (d, 1H), 7.28 (d, 1H) 6.98 (d, 1H), 6.86 (d, 1H), 5.5 (bs, OH), 4.04 (d, 1H), 4.00 (s, 3H), 3.8 (m, 2H), 3.60 (d, 1H), 2.60 (m, 6H), 1.55 (m, 4H), 1.43 (m, 2H). calculated mass for C23H26ClN3O4, 443.16, observed, 444.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>C(#N)C>[CH3:1][C:2]1[CH2:6][N:5]([C:7]([CH3:11])([CH3:12])[C:8]([O:10][CH2:28][CH:27]=[CH2:26])=[O:9])[C:4](=[O:13])[C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCBr
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOC(=O)C(C)(C)N1CC(C)=C(c2ccccc2)C1=O
Yield: 80.6 %

Procedure:
1.5 g (5.8 mmol) of 2-(4-methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl)isobutyric acid was dissolved in 50 ml of acetonitrile, and 0.83 g (6 mmol) of potassium carbonate and 0.73 g (6 mmol) of allyl bromide were added thereto. The mixture was refluxed under heating for 1 hour. After completion of the reaction, acetonitrile was distilled off, and ice water was added to the residue. The mixture was extracted with ethyl acetate. The extract was treated by a conventional method to obtain 1.7 g of a crude product. This crude product was purified by column chromatography to obtain 1.4 g (yield: 82%) of the desired product having a melting point of from 65° to 67° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[OH2:16].Cl.[OH-:18].[K+]>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:18])=[O:16])[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Br)ccc1C1(C#N)CCC1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: COc1cc(Br)ccc1C1(C(=O)O)CCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
The mixture of 1-(4-bromo-2-methoxyphenyl)cyclobutanecarbonitrile (370 mg, 1.04 mmol) in aqueous KOH (80%, 5 mL) and ethylene glycol (5 mL) was heated at 100° C. and stirred for 16 hours. The mixture was added water (20 ml) and acidified by concentrated HCl to pH=1 and extracted with dichloromethane. The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (327 mg, 82%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.19 (d, 1H), 7.13 (s, 1H), 7.12 (d, 1H), 3.72 (s, 3H), 2.59 (m, 2H), 2.30 (q, 2H), 2.05 (m, 1H), 1.78 (m, 1H)
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4].[CH2:25]([CH2:27][NH2:28])[OH:26]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[OH:26][CH2:25][CH2:27][NH:28][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4]
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Reactant: NCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(/C=C/c2c(-c3ccccc3)noc2C)sc1C(=O)NCCO
Yield: 61.9 %

Procedure:
To a stirred solution of 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (70 mg, 0.21 mmol) in toluene (0.5 mL) was added ethanolamine (15 mg, 0.25 mmol) and TBD (18 mg, 0.13 mmol). After 24 h the reaction mixture was diluted with brine and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated in vacuo, then purified by chromatography (silica, 0 to 10% methanol in dichloromethane) to give the title compound (48 mg, 60%) as a pale yellow oil. MS: m/e=370.1 [M+H]+.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[C:39](=[O:55])[CH:38]=[C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][N:33]=3)[CH:42]=[N:41]2)=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Yield: 92 %

Procedure:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 6a) instead of preparation 1c.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.S1[CH2:17][CH:16]=[C:15]([C:18]2[CH:19]=[CH:20][C:21]([N+:31]([O-:33])=[O:32])=[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)[CH:23]=2)[CH2:14][CH2:13]1.[O-:34][S:35]([O-:37])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl.O>[O:34]=[S:35]1(=[O:37])[CH2:13][CH:14]=[C:15]([C:18]2[CH:19]=[CH:20][C:21]([N+:31]([O-:33])=[O:32])=[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)[CH:23]=2)[CH2:16][CH2:17]1
Reactant: O=S([O-])[O-]
Reactant: CC1CCN(c2cc(C3=CCSCC3)ccc2[N+](=O)[O-])CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCN(c2cc(C3=CCS(=O)(=O)CC3)ccc2[N+](=O)[O-])CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 3-chloroperoxybenzoic acid (77 mg, 0.35 mmol, 77%) in 2 mL of DCM was added slowly to a solution of 1-[5-(3,6-dihydro-2H-thiopyran-4-yl)-2-nitro-phenyl]-4-methyl-piperidine (as prepared in the previous step, 50 mg, 0.16 mmol) in 2 mL of DCM at −78° C. under Ar. The mixture was stirred at −78° C. for 0.5 h, and then Warmed to RT. Treated with 2 mL of 10% Na2SO3 solution, the mixture was stirred vigorously for 5 min. The mixture was treated with 30 mL of EtOAc and 10 mL of H2O. The aqueous layer was separated and the organic layer was washed with saturated aq NaHCO3 solution (10 mL), H2O (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0-2% EtOAc/DCM) gave 35 mg (64%) of the title compound as a yellow oil: 1H-NMR (CDCl3; 400 MHz): δ 7.77 (d, 1H, J=8.6 Hz), 7.00 (d, 1H, J=1.9 Hz), 6.88 (dd, 1H, J=8.6, 1.9 Hz), 5.93 (m, 1H), 3.83 (br s, 2H), 3.24-3.30 (m, 4H), 3.11-3.17 (m, 2H), 2.83 (ddd, 2H, J=12.0, 12.0, 2.3 Hz), 1.72 (dd, 2H, J=12.6, 2.3 Hz), 1.53 (m, 1H), 1.35-1.47 (m, 2H), 1.00 (d, 3H, J=6.3 Hz). Mass spectrum (ESI, m/z): Calcd. for C17H22N2O4S, 351.1 (M+H), found 351.0.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[P:16](Cl)(Cl)([O:18][CH2:19][CH2:20][CH3:21])=[O:17]>CCOCC>[P:16]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:18][CH2:19][CH2:20][CH3:21])=[O:17]
Reactant: Oc1ccccc1O
Reactant: CCCOP(=O)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCOP1(=O)Oc2ccccc2O1
Yield: 101.8 %

Procedure:
Pyrocatechol (0.856 g, 7.77 mM) was dissolved in 32 ml of ether and, using 1.573 g (15.54 mM) of triethylamine and 1.484 g (7.77 mM) of n-propyl dichlorophosphate, the reaction was carried out at -30° C. to -25° C. and the reaction mixture treated in the same manner as in Reference Example 1. There was obtained 1.695 g (95.6% yield) of n-propyl o-phenylene phosphate as a viscous oil (slightly turbid).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[F:25]C1C=NC=C(F)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:25])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)ccn1
Temperature: 120 °C

Procedure:
In a 5 ml microwave reaction vessel were dissolved 70 mg (0.29 mmol) 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (Example 5) and 266 mg (2.31 mmol, 8.0 equiv.) of 3,5-difluoropyridine in 1.5 ml of DMF. Cesium carbonate (376 mg, 1.16 mmol, 4.0 equiv.) was added and the suspension was sonicated under argon for 10 min. The mixture was heated for 72 h at 120° C. in an oil bath and then 1 h at 160° C. under microwave irradiation. The dark brown suspension was filtered over Dicalite which was washed with ethyl acetate. The filtrate was evaporated to dryness in vaccuo, and the residue dissolved in 200 ml of ethyl acetate, which was washed once with brine. After drying over magnesium sulfate and concentration in vaccuo, the residue (90 mg) was purified by flash chromatography (gradient heptane/ethyl acetate 1:1 to 0:1 ) to yield the title compound, light yellow solid, (23 mg, 24%). MS (ISP): m/e=338.1 (M+H+).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:11]Br>C(Cl)Cl.[Fe]>[Br:11][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[C:2]([CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: BrBr
Reactant: Cc1ccccc1C(=O)O
Agent: [Fe]
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C(=O)O
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A mixture of o-toluic acid (28 g, 206 mmol), iron powder (0.74 g, 13 mmol), and Br2 (42 g, 260 mmol) were stirred at 0° for 2 hr. At this point the reaction, which had proceeded ˜40%, was diluted with 25 mL of CH2Cl2 to facilitate stirring. The reaction was then heated at 45° for 16 hr to drive to completion. Upon cooling, the reaction was diluted with CH2Cl2, washed 2× with 10% NaHSO3, 1× with brine prior to drying over Na2SO4. After removal of the volatiles, the residue comprising a 2:1 mixture of 5-bromo to 3-bromotoluic acid was recrystallized from 95% EtOH to yield 14.4 g of 5-bromo-2-methylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
A solution of 4-chlorophthalic anhydride (9.12 g, 500 mmol), aniline (4.65 g, 50 mmol), pyridine (12.01 g, 152 mmol) and DMAc (40 mL) was heated at 70° C. for 1 hour under argon. Acetic anhydride (20.0 g, 196 mmol) was added and the solution was allowed to stir at 80° C. for a total of 4 hours. The reaction mixture was cooled to ca. 5° C. and the crystalline solid removed by filtration, washed with acetone and methanol and dried in vacuo to give 9.0 g (70%) product which was recrystallized from acetic anhydride, mp 187°-189° C., (liturature melting point) 189.5°-191° C. 1H NMR(CDCl3) δ7.90 (d, J=1.6 Hz, 1), 7.88 (d, J=8.0 Hz, 1), 7.73 (dd, J=8.0, 1.6 Hz, 1), 7.50 (m, 2), 7.41 (m,3). 13C NMR (CDCl3) {1H} δ166.2, 165.9 141.1, 134.4, 133.5, 131.5, 129.9, 129.1, 128.2, 126.4, 124.9, 124.1.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH:11]1([CH2:14][C:15]#[N:16])[CH2:13][CH2:12]1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:15]([CH:14]([CH:11]1[CH2:13][CH2:12]1)[C:3]([O:7][CH2:8][CH3:9])=[O:10])#[N:16]
Reactant: CCOC(=O)OCC
Reactant: N#CCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)C1CC1

Procedure:
To a solution of sodium hydride (60% in mineral oil, 38 g) and diethyl carbonate (97 mL) in toluene (240 mL) was added dropwise a solution of cyclopropylacetonitrile (32 g) in toluene (120 mL) over 40 min with heating under reflux, and the mixture was heated under reflux for additional 2 hr. The mixture was neutralized with acetic acid (120 mL) in an ice bath, water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was distilled (boiling point 69-72° C., 4.0 mmHg) to give the title compound (50 g).