Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]2[C:17](=[O:18])[O:16][C:15](C)([CH3:19])[O:14][C:13]2=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)=O.C(N(CC)CC)C>C(O)C>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][CH:12]([C:17]([OH:18])=[O:16])[C:13]([O:14][CH2:15][CH3:19])=[O:21]
Reactant: COc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1OC
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)C(=O)O
Product: O

Procedure:
2.94 g (0.01 mol) of 5-(3,4-dimethoxyphenylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (m.p.: 142°-144° C.) and 0.83 ml of the mixture containing formic acid and triethylamine prepared as described in Example 1 were added to 8 ml of ethanol. After refluxing the reaction mixture for 6 hours, the method described in Example 25 was followed. The crude product was crystallized from a mixture of methanol and water.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26]N)=[N:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)=[N:24][CH:25]=1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-n3ccnn3)c2=O)nc1

Procedure:
171 mg (0.8 mmol) of the compound from Example 3A and 455 mg (purity 35%, 0.8 mmol) of the compound from Example 12A are initially introduced into 7 ml ethanol. 31 mg (0.2 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 64 h. Thereafter, it is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions are combined, the solvent is removed and the residue is dried under a high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(C2CCOCC2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(C2CCOCC2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (310 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. The reaction mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.41 g, 0.49 mL, 2.2 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL) The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (240 mg, 78%), which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.CN([CH:35]=[O:36])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:35]([OH:36])[N:10]([C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:8]2=[O:9]
Reactant: CN(C)C=O
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(C)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 79.5 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-4-methyl-N-(1-methyl-1-phenylethyl)benzamide (3.40 g, 10.9 mmol) was dissolved in THF (130 mL), and the solution was treated with TMEDA (5.20 mL, 34.5 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 36.5 mL, 34.7 mmol) and DMF (1.85 mL, 23.9 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=4/1 to 7/3 to 6/4). The obtained solid was purified by slurry using isopropylether and hexane to obtain 4-methoxymethoxy-5-methyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.96 g, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1.O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:7][CH:6]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1ncc(Cl)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Cl)cn1
Yield: 65.5 %

Procedure:
In a solution of 3.86 g of 2-amino-5-chloropyrimidine in 100 mL of pyridine, 10.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 23 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of 1,4-dioxane, a solution of 3.02 g of potassium hydroxide in 20 mL of water was added and stirred at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was diluted with 380 mL of water, precipitated crystal was filtered off, and washed with 150 mL of water. The resulting crude product was dissolved in 50 mL of ethyl acetate with heating, and 50 mL of 2N hydrochloric acid was added and stirred for 1 hour, and then 50 mL of toluene was added, and precipitated crystal was filtered off. Thereafter, the reaction mixture was washed with 50 mL of water, and then with 50 mL of toluene to obtain 7.95 g of the aimed product as white crystal. Melting point 137.0 to 141.0° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](O)[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:11]#[N:12].O=P(Cl)(Cl)[Cl:26]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]([Cl:26])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:11]#[N:12]
Reactant: N#CC(=C(O)c1ccc([N+](=O)[O-])cc1)c1nc2ccccc2s1
Reactant: O=P(Cl)(Cl)Cl
Product: N#CC(=C(Cl)c1ccc([N+](=O)[O-])cc1)c1nc2ccccc2s1
Temperature: 100 °C
Yield: 95 %

Procedure:
The above prepared 2-benzothiazol-2-yl-3-hydroxy-3-(4-nitrophenyl)-acrylonitrile (500 mg, 1.55 mmol) was suspended in POCl3 (12 mL). The suspension was heated at 100° C. for 4 hrs and was then poured into ice water (25 mL). The pH of the aqueous phase was adjusted to neutral. The solids were isolated by filtration and dried to yield 505 mg (95%) of 2-benzothiazol-2-yl-3-chloro-3-(4-nitrophenyl)-acrylonitrile. MS (m/z, ES+): 341.92 (Cl35M+1, 100%), 343.92 (Cl37M+1, 45%).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[CH3:27][O:28][C:29](=[O:49])[CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[OH:47])[C:32]1=[O:48]>>[CH3:27][O:28][C:29](=[O:49])[CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[OH:47])([CH2:5][OH:16])[C:32]1=[O:48]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: COC(=O)CN1C(=O)C(c2ccc(Cl)cc2O)c2ccccc21
Product: COC(=O)CN1C(=O)C(CO)(c2ccc(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with methyl[3-(4-chloro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: MS (ES+) m/z 362.5 (M+1) 364.5 (M+1).
Reaction SMILES: O[C@@H:2]([C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)[CH2:3][CH3:4].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].O.[N:17]1[CH:22]=CC=C[CH:18]=1>C(OC(=O)C)(=O)C>[CH3:18][N:17]([CH3:22])[C@@H:2]([C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)[CH2:3][CH3:4].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: c1ccncc1
Reactant: CC[C@@H](O)[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC[C@H]([c-]1cccc1)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10.0 g (38.6 mmol) of crude (R)-(1-hydroxypropyl)ferrocene in 10 ml of pyridine and 10 ml of acetic anhydride was stirred at room temperature for 18 hours. The reaction mixture was admixed with 50 ml of water and extracted three times with 200 ml each time of diethyl ether. The combined organic phases were dried over magnesium sulphate and evaporated on a rotary evaporator. The formation of the acetylated (R)-(1-hydroxypropyl)ferrocene can be followed by 1H NMR spectroscopy (δCHOAc =5.72-5.66, "dd", 1H). The crude (R)-(1-acetoxypropyl) ferrocene was stirred overnight at room temperature with 100 ml of isopropyl alcohol and 75 ml of dimethylamine (50% in water). The mixture was subsequently subjected to an aqueous work-up and extracted three times with 200 ml each time of diethyl ether. The combined organic phases were dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:29]1([C:34]2[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:41][CH2:40][C:38]2[CH:37]=[C:36]([C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:46][CH:47]=3)[N:35]=[C:34]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH:39]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 21.4 %

Procedure:
A solution of acid 4C (0.40 g, 1.45 mmol) in THF (20 mL) was added with DEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.51 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a white solid (0.18 g) after crystallization from ethyl ether. Yield=22%, 1HNMR (DMSO, 200 MHz) δ 1.95 (m, 4H), 2.95 (s, 3H), 3.46 (m, 4H), 4.36 (d, 2H), 5.12 (s, 1H), 5.86 (s, 1H), 6.52 (s, 1H), 7.22 (s, 1H), 7.73 (d, 2H, JO 7.9), 7.82-7.79 (m, 5H), 8.26 (d, 2H, J=7.8), 8.85 (t, 1H); [M+1] 579.03 (C27H26ClF3N4O3S requires 578.13).
Reaction SMILES: C=O.C([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=O)C1C=CC=CC=1.[CH2:17]([NH:24][CH2:25][C:26]([OH:28])=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:36]([C:13]12[CH2:12][CH2:11][C:26](=[O:28])[CH:25]1[N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:10][C:14]2=[O:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: Cc1ccccc1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: C=O
Solvent: O
Product: O=C1CCC2(Cc3ccccc3)C(=O)NN(Cc3ccccc3)C12
Temperature: 25 °C
Yield: 78 %

Procedure:
Paraformaldehyde (13.5 g) was added to a solution of N-benzylmaleimide (10.8 g; 60 mmol) and N-benzylglycine (9.9 g; 60 mmol) in toluene (400 mL) and the resulting mixture was refluxed with azeotropic removal of water, for 10 hours. The mixture was cooled to room temperature and was concentrated in vacuo. The mixture was purified by flash chromatography (30% EtOAc in hexane) to afford 15 g (78%) of the title product (I-1 a), as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](OC(OCC)OCC)(=O)C>C1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][N:8]=2)[CH:7]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: NNc1ccc(F)cn1
Solvent: C1CCCCC1
Product: Fc1ccc2nncn2c1
Yield: 70 %

Procedure:
(5-Fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) in diethoxymethyl acetate (5 mL) was stirred at RT for 2 h. The resulting precipitate was diluted with cyclohexane (5 mL) and filtered to give the title compound (379 mg, 70%). 1H NMR (400 MHz, CDCl3): 7.25 (1H, m), 7.84 (1H, m), 8.09 (1H, t), 8.84 (1H, s).
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([OH:11])=O)=[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:25]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:30])(=[O:27])=[O:26])=[CH:15][CH:14]=3)[N:6]([CH2:37][CH2:38][CH3:39])[N:5]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:42]1C=CN=C1)=O.N.CCO>C1COCC1>[CH:1]1([C:4]2[C:8]([C:9]([NH2:42])=[O:11])=[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:25]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:30])(=[O:27])=[O:26])=[CH:15][CH:14]=3)[N:6]([CH2:37][CH2:38][CH3:39])[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCCn1nc(C2CC2)c(C(=O)O)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CCCn1nc(C2CC2)c(C(N)=O)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of the compound obtained in example 60 (0.15 g, 0.28 mmol) in THF (10 mL) was added 1,1'-carbonyldiimidazole (0.057 g, 0.35 mmol) and the mixture was stirred at room temperature under an argon atmosphere for 3 h. Next, ammonia (32% aqueous solution, 0.33 mL) and EtOH (0.7 mL) were added and the reaction mixture was stirred at room temperature overnight and then at reflux for 1 h. The solvent was removed, the residue was taken up in CH2Cl2 and H2O was added. The aqueous phase was acidified to pH=6 and extracted with EtOAc. The combined organic extracts were dried and concentrated to a crude product. This was chromatographed on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compound as a white solid (40%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
A solution of 4-nitrobenzenethiol (Aldrich, 2.5 g; 16.1 mmol) in acetone (110 ml) was treated with potassium carbonate (2.22 g; 16.1 mmol) and ethyl 4-bromobutanoate (Aldrich, 3.43 g; 17.6 mmol). After stirring at RT for 18 hours, the mixture was filtered and the solid washed with acetone. The organic fractions were combined and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of Et2O to give the title compound as an off-white solid (4.0 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH3:11][CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20].O>CCCCCC>[CH3:11][CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1ccc(CO)cc1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
4-Methoxybenzyl alcohol (603 mg, 4.35 mmol), 8-methylnonanoic acid (750 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 4-methoxybenzyl 8-methylnonanoate (1.15 g, yield 90.2%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:10](CC)[C:9]([C:13]3C(N)=NON=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.ClCCl>[Br:1][C:2]1[C:3]([NH:10][CH2:9][CH3:13])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCNc1c(N)cncc1Br
Temperature: 25 °C

Procedure:
A solution of the product of Step 1 (0.5 g, 2 mmol) in ethanol (8 ml)/water (10 ml) was stirred at 60° C. and sodium dithionite (2.12 g, 12.2 mmol) was added protionwise. After 10 minutes the mixture was cooled to room temperature, and diluted with water and dichloromethane. The organic phase was dried and evaporated in vacuo, the residue was used directly in the next reaction; 1H NMR (DMSO-d6) 7.76 (1H, s), 7.75 (1H, s), 5.0 (2H, br), 4.46 (1H, t, J=9.6 Hz), 3.26 (2H, m), 1.06 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[C:17]1([CH:23]2[CH2:25][O:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C)C>O1CCOCC1>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][C:2]([NH:1][CH2:25][CH:23]([OH:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15])(=[O:11])[NH2:12]
Reactant: CC(C)(N)COc1ccc(O)c(C(N)=O)c1
Reactant: c1ccc(C2CO2)cc1
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)NCC(O)c1ccccc1

Procedure:
A solution of 4.5 g of 5-(2-amino-2-methyl-propoxy)-salicylamide and 3.1 g of 2-phenyloxirane in 40 ml of dioxane is refluxed for 16 hours. The solvent is subsequently evaporated off under reduced pressure, and the residue is dissolved in 20 ml of 2N hydrochloric acid, and extracted with 50 ml of ether. The water phase is separated; it is rendered alkaline with concentrated ammonia, and the liberated base is extracted with 200 ml of ethyl acetate. Customary further processing yields a light-coloured foam, from which is obtained, by recrystallisation from isopropanol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1,1-dimethyl-ethyl]-aminomethyl]-benzyl alcohol, m.p. 121°-123°. It forms a neutral fumarate, m.p. 209°-210° (from methanol).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]([F:22])[F:21])=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[F:21][CH:20]([F:22])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:19][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(CN)ccc1C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc(C(F)F)c(C(=O)O)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Add isobutyryl chloride (0.571 mL, 5.42 mmol, 1.05 equiv) to a mixture of methyl 5-(aminomethyl)-2-(difluoromethyl)benzoate hydrochloride (1.30 g, 5.17 mmol, 1.0 equiv) and triethylamine (1.51 mL, 10.85 mmol, 2.1 equiv) in DCM (50 mL) at room temperature and stir the mixture for one hour. Dilute the mixture with DCM; wash with water; then with a saturated sodium chloride aqueous solution. Separate the organic layer; dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure. Dissolve the resulting crude material in 1,4-dioxane (10 mL), and add sodium hydroxide (5 N, 2 mL, 10 mmol, 1.93 equiv). Stir the resulting suspension at 40° C. overnight. Concentrate the mixture under reduced pressure, and treat the resulting residue with 1 N aqueous hydrochloric acid until the pH reaches 3. Extract the resulting suspension with EtOAc (2×30 mL). Wash the combined organic layers with a saturated sodium chloride aqueous solution (50 mL); dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure to give the title compound as a white solid (1.32 g, 94% yield). ES/MS (m/z) 272 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:20]
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C=O)c1
Temperature: 25 °C

Procedure:
Under N2 in a flame-dried 3-neck round bottomed flask fitted with a reflux condenser and magnetic stirrer, a mixture of 5-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde (3.0 g, 8.7 mmol), zinc (II) cyanide (1.5 g, 13 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.5 g, 1.3 mmol) in anhydrous DMF (145 ml) was stirred at room temperature while degassing with N2 for 5 min. After heating at approximately 80° C. for 90 min., the reaction was judged complete by thin layer chromatography (50% CH2Cl2:hexanes) and was allowed to cool to room temperature. The reaction mixture was then diluted with water and ethyl acetate (EA) and stirred another 10 min. The water layer was separated, extracted twice with EA and combined with the original EA layer, and washed with an aqueous solution of Rochelle salt (potassium sodium tartrate tetrahydrate) followed by aqueous NaCl. The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to an oil. The oil was flash chromatographed on a 15×5 cm column of silica gel, eluting with CH2Cl2:hexanes (1:1) to obtain the title product as a white solid, 1.5 g (60%), m.p. 122–126° C.