Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH2:9][OH:10].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH2:9][O:10][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1ccc(Cl)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1COc1cccc(F)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a cold (ice water) suspension of sodium hydride (472 mg; 11.8 mmol) in anhydrous DMF (5 mL) is added a solution of 5-chloro-2-methoxybenzyl alcohol (1.72 g; 9.7 mmol) in anhydrous DMF (5 mL) over 15 minutes. After allowing to room temperature over 1 hour, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.63 g; 11.3 mmol) in anhydrous DMF (8 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 45° C. overnight to give 2.28 grams of 2-(5-chloro-2-methoxybenzyloxy)-6-fluorobenzonitrile.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[N+:5]([O-])[C:4]=2[CH:3]=[CH:2]1.[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.C(Cl)Cl>[CH2:15]([C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4]=2[N:5]=1)[CH3:16]
Reactant: CC[Mg]Br
Reactant: [O-][n+]1cc2ccccc2c2sccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nc2ccsc2c2ccccc12
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A suspension of Thieno[3,2-c]isoquinoline 4-oxide (20 g, 99 mmol) in dry tetrahydrofuran (ca. 400 mL) was treated dropwise at −78° C. with an ethereal solution of ethylmagnesium bromide (3.0 M, 40 mL, 120 mmol) during 10 min. After 6 h the reaction mixture was quenched with 2 N aqueous hydrochloride acid (75 mL) and stirred for ca. 10 min. At this time the solution was treated with 2.5 N aqueous sodium hydroxide (65 mL). The resulting gelatinous residue was diluted with water (400 mL), filtered through Celite, and the filtrate was extracted with ethyl acetate (3×500 mL). The combined extracts were washed with water and brine (1.5 L each), dried (K3CO3) and concentrated in vacuo to give the crude product (19 g) as an orange oil which was taken up in methylene chloride (ca. 60 mL) and pre-adsorbed on silica gel (60 g). Flash chromatography on silica gel (740 g) eluting 2.5-, then 5-, and then 10% ethyl acetate-hexane provided the title compound (17 g, 81%, m.p. 39-41° C.) as a clear, pale yellow oil which crystallized on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].IC.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:15])[C:8](=[O:11])[C:7]2=[O:12]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(=O)c2cccc(F)c21

Procedure:
7-Fluoro-1H-indole-2,3-dione (5, prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325, 3.00 g, 0.182 mol), iodomethane (3.40 ml, 0.545 mol) and potassium carbonate (4.92 g, 0.0363 mol) in DMF (15 ml) are stirred at room temperature for 1 hour. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as a solid. HPLC r.t. 4.01 min; MS for C9H6FNO2 m/z 180.0 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 27.6 %

Procedure:
6.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-galactopyranosylurea are dissolved in 15 ml of formic acid, and 4.2 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further strirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:20][O:21]C2CCCCO2)[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].C(Cl)Cl>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:20][OH:21])[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: Cc1cc(F)ccc1C(CCOC1CCCCO1)CN(C)C(=O)c1cc(C#N)cc2c1CCCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(CCO)CN(C)C(=O)c1cc(C#N)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
3-Cyano-N-[2-(4-fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (460 mg, 0.96 mmol) was dissolved in methanol (10 mL) together with 4-toluenesulfonic acid (37 mg, 0.2 mmol) and the solution was stirred at room temperature overnight. An aqueous solution of NaHCO3 together with CH2Cl2 was added and the organic solution was then washed with brine, dried and the solvent removed by evaporation. There was obtained 350 mg (92%) of 3-cyano-N-[2-(4-fluoro-2-methylphenyl)-4-hydroxybutyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil. 1H NMR (300 MHz, CDCl3): 1.0-2.3 (cm, 6H), 2.4 (s, 3H), 2.6 (s, 3H), 2.7-4.5 (cm, 10H), 6.4-7.4 (cm, 5H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)=[C:5]([O:18][CH2:19][C:20]#[CH:21])[CH:4]=1.C([O-])(=O)/C=C/[C:25]([O-])=[O:26]>>[CH3:25][O:26][C:8]1[CH:7]=[C:6]([C:9]2[NH:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[C:5]([O:18][CH2:19][C:20]#[CH:21])=[CH:4][CH:3]=1
Reactant: C#CCOc1cc(OC)ccc1-c1nc2ncccc2[nH]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: C#CCOc1ccc(OC)cc1-c1nc2ncccc2[nH]1

Procedure:
2-(4-Methoxy-2-propargyloxyphenyl)imidazo(4,5-b)-pyridine, fumarate, m.p. 220°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([OH:34])[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4([CH3:33])[O:32][CH2:31][CH2:30][O:29]4)[CH:24]=3)[CH:19]=2)[CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4([CH3:33])[O:29][CH2:30][CH2:31][O:32]4)[CH:24]=3)[CH:19]=2)=[O:34])[CH:12]=1
Reactant: CC1(c2ccc3cc(C(O)c4cccnc4)ccc3c2)OCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(c2ccc3cc(C(=O)c4cccnc4)ccc3c2)OCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
A solution of 165 mg of oxalyl chloride in 20 ml of methylene chloride was cooled to -50° C., 203 mg of dimethylsulfoxide added dropwise, and the mixture stirred for 5 minutes. A solution of 321 mg of 2-[(3-pyridyl)hydroxymethyl]-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene in 10 ml of methylene chloride was then added dropwise and the mixture stirred at -50° C. for 15 minutes. Triethylamine (506 mg) was added at -50° C. and the mixture stirred for 5 minutes, then allowed to warm to room temperature. The solution was washed with water, dried over sodium sulfate and the solvent removed under reduced pressure to give 300 mg of 2-(3-pyridylcarbonyl)-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8][CH2:7][NH:6]1)=O>C1(C)C(C)=CC=CC=1>[CH2:14]([N:13]1[CH2:12][CH2:11][CH2:10][C:5]2([NH:6][CH2:7][CH2:8][CH2:9]2)[C:3]1=[O:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1(CCCNCc2ccccc2)CCCN1
Solvent: Cc1ccccc1C
Product: O=C1N(Cc2ccccc2)CCCC12CCCN2
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A solution of 2-(3-benzylaminopropyl)pyrrolidine-2-carboxylic acid methyl ester (133 mg) in xylene (1.5 ml) was stirred at 130° C. overnight. The mixture was cooled to room temperature, and purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (90 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1.O>CN(C=O)C>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
A mixture of 8.75 g (63.4 mmol) of K2CO3, 9.25 g (86.4 mmol) of 2-methylaniline and 20.0 g (57.6 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 450 ml of DMF was stirred at 80° C. for 12 h. The resulting mixture was poured into 100 cm3 of water, and the product was extracted with 3×250 ml of ethyl acetate. The combined organic extract was dried over MgSO4 and then evaporated to dryness. Crystallization of this crude product from 250 ml of hexanes gave 14.4 g (67%) of brown crystals of the title compound. Anal. Calc. for C24H2813NO2: C, 77.22; H, 7.56; N, 3.75. Found: C, 77.39; H, 7.70; N, 3.64. 1H NMR (CDCl3): 8.20 (m, 1H, 8-H in naphthyl), 7.84 (d, J=8.5 Hz, 1H, 4-H in naphthyl), 7.82 (m, 1H, 5-H in naphthyl), 7.43-7.52 (m, 3H, 3,6,7-H in naphthyl), 7.14 (m, 1H, 5-H in Ph), 7.06 (m, 1H, 3-H in Ph), 6.79 (m, 1H, 6-H in Ph), 6.68 (m, 1H, 4-H in Ph),
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].[CH:18](=[N:22][OH:23])[C:19]([CH3:21])=O>CC(O)C>[NH2:15][C:14]1[C:13]([C:16]#[N:17])=[N:12][C:19]([CH3:21])=[CH:18][N+:22]=1[O-:23]
Reactant: N#CC(N)C#N
Reactant: CC(=O)C=NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1c[n+]([O-])c(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
Aminomalononitrile p-toluenesulfonate salt (20.0 g, 79 mmol) and pyruvaldehyde 1-oxime (6.88 g, 79 mmol) were combined in a flask. iPrOH (140 mL) was added, and the resulting yellow slurry was allowed to stir at room temperature for 18 h, during which time a yellow precipitate accumulated. The mixture was filtered and the precipitate was washed with iPrOH (2×50 mL) and DI H2O (20 mL), then lyophilized to give 2-amino-3-cyano-5-methypyrazine N-oxide (10.7 g).
Reaction SMILES: FC1C=CC(S(Cl)(=O)=O)=C(C)C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]([C:34](OCC)=[O:35])=[CH:24]2)(=[O:22])=[O:21])=[C:16]([CH3:39])[CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]([CH:34]=[O:35])=[CH:24]2)(=[O:21])=[O:22])=[C:16]([CH3:39])[CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2C)c1
Agent: Cc1cc(F)ccc1S(=O)(=O)Cl
Product: Cc1cc(F)ccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1

Procedure:
Using 4-fluoro-2-methylbenzenesulfonyl chloride instead of tosyl chloride, a procedure as in Reference Example 4 was performed to synthesize ethyl 1-[(4-fluoro-2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate, and procedures as in Reference Examples 5 and 6 were sequentially performed to give the title compound as a pale-yellow oil.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](O)([C:16]([F:19])([F:18])[F:17])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])C.[NH3:21]>>[C:10]1([C:7]2[C:8]([NH2:9])=[N:21][CH:4]=[CH:5][C:6]=2[C:16]([F:19])([F:18])[F:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC=CC(O)(C(C#N)c1ccccc1)C(F)(F)F
Reactant: N
Product: Nc1nccc(C(F)(F)F)c1-c1ccccc1
Temperature: 125 °C
Yield: 57.7 %

Procedure:
50 g of 5-ethoxy-3-hydroxy-2-phenyl-3-trifluoromethylpent-4-enenitrile were mixed with 600 g of aqueous ammonia (25%), and the resulting mixture was heated to 125° C. in an autoclave for 24 h. Subsequently, the reaction mixture was cooled and the resulting biphasic mixture was extracted repeatedly with dichloromethane. The combined organic phases were concentrated by rotary evaporation and the product was subsequently recrystallized from heptane. 24.1 g of 3-phenyl-4-trifluoromethylpyridin-2-ylamine (52% over both stages) were thus isolated.
Reaction SMILES: C(=O)([O-])O.[Na+:5].[OH-].[Na+].O.Cl.[NH:10]=[C:11]1[NH:15][C:14]([C:16](=[N:44][OH:45])[C:17]([NH:19][CH:20]2[C:42](=[O:43])[N:22]3[C:23]([C:39]([OH:41])=[O:40])=[C:24]([CH2:27][O:28]C(=O)C(C4C=CC=CC=4)O)[CH2:25][S:26][C@H:21]23)=[O:18])=[CH:13][S:12]1>>[NH:10]=[C:11]1[NH:15][C:14]([C:16](=[N:44][OH:45])[C:17]([NH:19][CH:20]2[C:42](=[O:43])[N:22]3[C:23]([C:39]([O-:41])=[O:40])=[C:24]([CH2:27][OH:28])[CH2:25][S:26][C@H:21]23)=[O:18])=[CH:13][S:12]1.[Na+:5]
Reactant: N=c1[nH]c(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(COC(=O)C(O)c4ccccc4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N=c1[nH]c(C(=NO)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(CO)CS[C@H]23)cs1
Reaction time: 1 h

Procedure:
In 5 ml of there was dissolved 0.57 g of 7-[2-(2-imino-4-thiazolin-4-yl)-2-hydroxyimino-acetamido]-3-(mandelyloxymethyl)-3-cephem-4-carboxylic acid hydrochloride (syn-isomer) together with 0.17 g of sodium hydrogen carbonate and, while the mixed solution was stirred under ice-cooling, 0.55 ml of 2N-sodium hydroxide was added. The mixture was stirred at that temperature for 3 hours and, then, at room temperature for 1 hour. The reaction mixture was subjected to column chromatography on polystyrene resin (Amberlite XAD-2, Rohm and Haas Co.), development being carried out with water. The fractions containing the desired product were pooled and lyophilized. By the above procedure there was obtained 0.19 g of the captioned compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].Cl[C:10](Cl)([O:12]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:10]=[O:12]
Reactant: Nc1ccccc1I
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C=Nc1ccccc1I
Reaction time: 4 h
Yield: 267.4 %

Procedure:
A solution of 2-iodo-phenylamine (30 g, 0.14 mol) in dichloromethane (800 ml) was added triphosgene (14.6 g, 49.3 mmol) and saturated sodium bicarbonate (544 ml) at 0° C. The resulted mixture was stirred for 4 hours. The organic layer was washed with brine (200 ml) and dried over sodium sulfate. After removal of solvent, the crude product 1-iodo-2-isocyanato-benzene (32.3 g, 96%) was obtained as a yellow oil which was used in next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.[BrH:11]>>[BrH:11].[Br:11][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Agent: Br
Product: Nc1ccc(CCBr)cc1

Procedure:
To 4-aminophenethyl alcohol (25 g) was added 48% hydrobromic acid (250 ml), and the mixture was heated under reflux for 4 hours with stirring. After cooling, collection of the resulting precipitates by filtration gave 4-(2-bromoethyl)aniline hydrobromide (30.3 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]([OH:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)=[CH:4][CH:3]=2)=[C:25]([OH:27])[CH:26]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)OB(c2ccc(Cl)cc2O)OC1(C)C
Product: CN(c1ccc(-c2ccc(Cl)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Intermediate 1-1 and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol were reacted according GENERAL METHOD 1-5 for Suzuki coupling. 5-Chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol was obtained as a yellow solid after HPLC purification. LCMS Rt=0.54 min [Method Q], MS (M+1)=375.2. 1H NMR (METHANOL-d4) δ 8.16 (d, J=9.6 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.45 (d, J=10.1 Hz, 1H), 6.91-7.05 (m, 2H), 5.28-5.44 (m, 1H), 3.06 (s, 3H), 1.88-2.05 (m, 4H), 1.65 (s, 6H), 1.52 (s, 6H).
Reaction SMILES: [C:1]([O:9][C:10]1[C:27]([O:28][CH3:29])=[CH:26][C:13]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22](OC)=[O:23])=[O:15])=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10]1[C:27]([O:28][CH3:29])=[CH:26][C:13]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH:22]=[O:23])=[O:15])=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCCCN1C(=O)c1cc(OC)c(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2CCCC[C@@H]2C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
(R)-Methyl 1-(4-(benzoyloxy)-5-methoxy-2-nitrobenzoyl)piperidine-2-carboxylate (1.50 g, 3.50 mmol) in 30 ml of 1:1 DCM/benzene at −78° C. was added 7.5 ml of 1.0 M DIBAL in toluene under Ar in 10 min. The mixture was stirred at −78° C. for 1 hr and the reaction was quenched with 0.5 ml of methanol. The mixture was diluted with 150 ml of EtAc and 100 ml of 0.2 M HCl. The organic solvent layer was separated and was separated and the aqueous layer was extracted with EtOAc (3×80 ml). The organics were combined, dried over MgSO4, filtered, concentrated and purified on SiO2 chromatography eluted with EtAc/hexane (3:2) to afford 1.52 g (90%) of the title product. 1H NMR (CDCl3), 9.60 (s, 1H), 7.70 (s, 1H), 7.65-7.28 (m, 5H), 6.78 (m, 1H), 5.16 (s, 2H), 3.92 (s, 3H), 3.22, (m, 1H), 3.01 (m, 1H), 2.20 (m, 1H), 1.84 (m, 1H), 1.65-1.40 (m, 4H); 13C NMR 200.24, 171.31, 155.13, 154.78, 148.41, 146.20, 137.57, 135.47, 129.03, 128.73, 127.31, 109.83, 109.41, 71.61, 64.50, 56.96, 45.98, 25.25, 23.42, 18.70; MS m/z+421.1 (M+Na).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:40]([NH2:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:45][CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)CN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCC(C)(C)C)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and neopentylamine.
Reaction SMILES: [CH3:1][CH:2]1[NH:4][CH2:3]1.[OH-].[Na+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>O1CCCC1>[CH3:1][CH:2]1[N:4]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([Cl:7])=[CH:9][CH:10]=2)=[O:13])[CH2:3]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC1CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CN1C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
A solution of propyleneimine (12 mL, 0.15 mol) in tetrahydrofuran (160 mL) was added to 1N aqueous sodium hydroxide solution. To this mixture was added dropwise 4-chlorobenzoyl chloride (25 g, 0.14 mol) at 0° C. After the completion of the dropwise addition, the mixture was further stirred for 30 min. The reaction mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated to give the title compound (25 g, yield 89%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH2:12])=[S:11].CCN(C(C)C)C(C)C.Br[CH:25]([C:31](OCC)=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CCO.CCOC(C)=O>[O:32]=[C:31]1[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:13])([F:1])[F:14])=[N:12]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: NC(=S)Nc1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1SC(Nc2ccccc2C(F)(F)F)=NC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)phenylthiourea (Menai Organics, 2.36 g, 10.7 mmol), Hunig's base (Aldrich, 1.9 mL, 10.7 mmol) in EtOH (10 mL) was added diethyl bromomalonate (2.0 mL, 10.7 mmol). After 1.5 h at room temperature, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 333 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[C:8]([O:16]CC)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1>>[C:4]1(=[O:6])[NH:5][C:1](=[O:7])[CH2:2][CH2:3]1.[C:8]([NH2:5])(=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1
Reactant: CCOC(=O)c1cccnc1
Agent: O=C1CCC(=O)N1
Product: NC(=O)c1cccnc1
Temperature: 150 °C
Yield: 4734.8 %

Procedure:
Succinimide (2100 number average molecular weight, 368.8 g, 0.073 mol) and ethyl nicotinate 11.1 g (0.073 mol) were charged to a 250 mL resin kettle equipped with an overhead stirrer, a Dean-Stark trap and a thermocouple. The reaction mixture was heated under a nitrogen atmosphere to 150° C. for 3 hours. The reaction mixture was diluted with 44.6 g process oil to afford 382.3 g of desired product.
Reaction SMILES: O1C2C=CC=CC=2C(C2C=CC(OCC(O)=O)=C(C)C=2[Cl:22])=N1.C([O:27][C:28](=[O:48])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[O:39][N:38]=2)=[C:33]([CH3:46])[C:32]=1C)CCC.C(NC1C=CC2ON=C(C3C=CC(OCC(O)=O)=C(Cl)C=3Cl)C=2C=1)(=O)C.ClC1C=CC2ON=C(C3C=CC(OCC(O)=O)=C(Cl)C=3Cl)C=2C=1>>[O:39]1[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:28]([OH:27])=[O:48])=[C:32]([Cl:22])[C:33]=2[CH3:46])=[N:38]1
Reactant: CCCCOC(=O)COc1ccc(-c2noc3ccccc23)c(C)c1C
Reactant: Cc1c(OCC(=O)O)ccc(-c2noc3ccccc23)c1Cl
Agent: CC(=O)Nc1ccc2onc(-c3ccc(OCC(=O)O)c(Cl)c3Cl)c2c1
Agent: O=C(O)COc1ccc(-c2noc3ccc(Cl)cc23)c(Cl)c1Cl
Product: Cc1c(-c2noc3ccccc23)ccc(OCC(=O)O)c1Cl

Procedure:
4-(1,2-benzisoxazol-3-yl)-3-chloro-2-methylphenoxyacetic acid; butyl-4-(1,2-benzisoxazol-3-yl)-2,3-dimethylphenoxyacetate; pentyl (4-(1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetate; 4-(6-bromo-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(5-ethyl-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(5-nitro-1,2-benzisoxzaol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(6-amino-1,2-benzosoxazol-3-yl)-2,3-dichlorophenoxyacetic acid); 4-(5-acetamido-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(5-chloro-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid;