Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH:11]([Cl:14])[CH2:12][CH3:13].[OH-].[K+]>C(O)C>[Cl:14][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: CCC(Cl)Br
Reactant: OCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(OCCCCl)cc1

Procedure:
A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated wtih 1, 3 bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2 H, J=8.8 Hz), 6.88 (d, 2 H, J=8.8 Hz), 5.03 (t, 1 H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2 H, J=6.1 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS eI m/z 200.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH2:16]([Mg]Br)[CH3:17].[Cl-].[NH4+]>CCOCC>[OH:2][CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[CH:5][CH:4]=1)[CH2:16][CH3:17]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in ether (300 ml), followed by the dropwise addition of ethylmagnesium bromide (3M ethereal solution, 33 ml) under cooling with ice. The obtained mixture was stirred to complete a reaction. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ether. The organic phase was distilled to remove the solvent and the obtained residue was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 22.3 g of t-butyl 4-(1-hydroxypropyl)benzoate. This product was dissolved in petroleum ether (500 ml), followed by the addition of active manganese dioxide (165 g). The obtained mixture was heated under reflux for 30 hours to complete a reaction. The reaction mixture was filtered and the filtrate was concentrated to give 21.1 g of t-butyl 4-propionylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[NH:9][CH:8]=[N:7][C:6]=2[N:12]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:10]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2nc(F)ccc12
Product: Fc1ccc2c(Cl)ncnc2n1

Procedure:
A suspension of 7-fluoropyrido[2,3-d]pyrimid-4(3H)-one (0.20 g, 1.21 mmol) in POCl3 (10 mL) is heated under reflux for 2 h. The volatiles are then removed under reduced pressure, and the residue is partitioned between aqueous NaHCl and EtOAc. The organic extract is worked up to give crude 4-chloro-7-fluoropyrido[2,3-d]pyrimidine, which is used directly in the next reaction. A solution of this product (0.20 g, 1.09 mmol) and 3-bromoaniline (0.23 mL, 2.18 mmol) in propan-2-ol (1.0 mL) and THF (10 mL) containing a trace of conc. HCl is stirred at 20° C. for 1 h, and then concentrated to dryness. The residue is dissolved in EtOAc, washed with aqueous NaHCO3, and worked up to give an oil, which is chromatographed on silica gel. Elution with EtOAc/petroleum ether (1:5) gives 3-bromoaniline, while EtoAc/petroleum ether (1:1) elutes 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (0.18 g, 47%), mp (MeOH) 211°-213° C. 1H NMR (DMSO) δ 10.18 (1H, brs), 9.17 (1H, t, J=8.6 Hz), 8.80 (1H, s), 8.17 (1H, t, J=1.8 Hz), 7.85 (1H, dt, Jd =7.6 Hz, Jt =1.8 Hz), 7.53 (1H, dd, J=8.6, 2.7 Hz), 7.41-7.34 (2H, m).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][Br:31])[CH:25]=1>CC#N>[Br-:31].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: COc1cccc(CBr)c1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Solvent: CC#N
Product: COc1cccc(C[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)C3)c1
Product: [Br-]
Yield: 9.9 %

Procedure:
Following the general procedure outlined in Example 1, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (29.3 mg, 0.105 mmol) and 3-(bromomethyl)phenyl methyl ether (0.03 mL, 0.21 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (5 mg, 10%). EI-MS m/z 400 (M+) Rt (1.72 min).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].Cl.[CH3:12][O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16].C([O-])(=O)C.[Na+].C(O)(=O)C>C(OCC)(=O)C>[CH3:12][O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:16][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Yield: 65.5 %

Procedure:
In 100 g of ethyl acetate, 14.3 g (0.1 mole) of N-formyl-L-aspartic anhydride and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride were suspended and 9.2 g (0.11 mole) of sodium acetate was added to the suspension during 30 minutes at 20°-25° C. with stirring. The mixture was reacted for 5 hours with stirring at the same temperature. Thereafter 14.3 g of acetic acid was added and stirred for an hour at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in a yield of 21.1 g (65.5% yield on L-Phenylalanine methyl ester hydrochloride). The crystals obtained were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 98.0:2.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18](=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1CN(C(=O)c2ccc(F)cc2)CCN1
Reaction time: 2 h

Procedure:
Add 25.0g (0.158 mol) of p-fluorobenzoyl chloride drop-wise to a 0° C. solution of 15.0 g (0.150 mol) of N-methylpiperazine and 20.0 g (0.189 mol) of sodium carbonate in 100 mL of water. Stir the resultant solution at 0° C. for about 30 minutes, then at room temperature for about 2 hr. Extract the resultant solution with methylene chloride (2×100 mL). Dry the combined extracts with Na2SO4 and evaporate the solvent to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][CH:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]1[NH2:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:42][CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:40][CH2:41][CH:32]1[CH3:31])=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: CC1CCc2ccccc2C1N
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2c3ccccc3CCC2C)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methyl-1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: O=[C:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C(O)C>[O:10]=[C:8]1[NH:20][C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:19]=[C:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2ccccc2[nH]c1=O
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.8 %

Procedure:
Diethyl ketomalonate (8 g) was added to an ethanol (100 ml) solution of 1,2-phenylenediamine (5 g). The reaction mixture was stirred at 50° C. for 14 hours. The precipitated crystals were filtrated, which was washed with IPE to obtain the entitled compound (8.2 g).
Reaction SMILES: CC(=CC)C.B#B.[CH3:8][C:9]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:11]#[CH:12].[Br:25]Br>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[Br:25]/[CH:12]=[CH:11]/[CH:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:9]([CH3:24])([CH3:8])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: BrBr
Reactant: C#CC(OC1CCCCO1)C(C)(C)CCCC
Agent: B#B
Agent: CC=C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(/C=C/Br)OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of 3.5 g. (50 moles) of 2-methyl-2-butene in 25 ml. of tetrahydrofuran under an inert atmosphere is added 25 ml. of 1 M diborane in tetrahydrofuran dropwise over 10 minutes. The mixture is stirred at 0°-5° C. for 2 hours and then the solvent is removed under vacuum. The residue is dissolved in 20 ml. of carbon tetrachloride and to the resulting solution cooled to 0° C. is added a solution of 5.25 g. (22 moles) of 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 995) in 10 ml. of carbon tetrachloride over 10 minutes. The cooling bath is removed and the mixture is allowed to stir at ambient temperature for 1.5 hours. The mixture is cooled to 0° C. and a solution of 3.52 g. (22 moles) of bromine in 15 ml. of carbon tetrachloride is added over 10 minutes. The cooling bath is removed and the mixture is refluxed for 6 hours under an inert atmosphere. The mixture is cooled and poured into dilute sodium hydroxide solution. The organic phase is washed with water and saturated brine, dried (Na2SO4), and evaporated. The residue is chromatographed upon silica gel and the title compound is isolated with 5% ethyl acetate in benzene.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:6][N:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@H](C2C=CC=CC=2)C)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3][CH2:4][N:5]([C@H:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(O)(c2ccccc2)CC1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](c1ccccc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of (S)-1-phenylethyl (R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate (0.350 g, 0.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 2 hours. The volatiles were subsequently removed in vacuo and the residue was purified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm; CH3CN—H2O-0.1% TFA) to give the title compound (as TFA salt) as a white solid (0.230 g, 88%). LCMS: Anal. Calcd. for C19H21NO3: 311. found: 312 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH3:15])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Cl)=[O:7].C(N(C(C)C)CC)(C)C>O>[O:7]=[C:6]1[C:8]2[C:13](=[CH:12][CH:11]=[N:10][CH:9]=2)[NH:3][CH:4]([CH3:15])[CH2:5]1
Reactant: CC(N)CC(=O)c1cnccc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(=O)c2cnccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[Step 3] 64 mg of the crude product of 3-amino-1-(4-chloropyridin-3-yl)butan-1-one dihydrochloride were dissolved in 2 mL of N-dimethylformamide followed by adding 0.18 mL of diisopropylethylamine while cooling with ice and stirring for 1 hour at room temperature. This was followed by additionally stirring overnight at 100° C. Following completion of the reaction, water was added followed by extracting three times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (methanol:chloroform=1:10) to obtain 9 mg of 4-oxo-2-methyl-2,3-dihydro-1H-[1,6]naphthyridine in the form of a pale yellow oil (27%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.Cl.[NH2:14][C:15]([CH3:28])([CH3:27])[C:16](=[N:25][OH:26])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:14][C:15]([CH3:28])([CH3:27])[C:16](=[N:25][OH:26])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:7]=1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(N)C(COc1ccccc1)=NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(COc1ccccc1)=NO
Yield: 48.1 %

Procedure:
A mixture of 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal = Cl) (1.53 g), 3-amino-1-(p-methoxy)phenoxy-3-methylbutan-2-one oxime hydrochloride (IV) (2.2 g) and dry triethylamine (1.70 g) in dry ethanol (20 ml) was refluxed for 2 hours. The mixture was cooled, water (50 ml) was added, and the resulting precipitate was filtered off and dried. Recrystallisation from a mixture of water and ethanol gave the nitropyrimidine oxime (II) (1.4 g, yield 48%) as pale yellow crystals, m.p. 242° (decomp.).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:32][C:33](=O)[CH2:34][C:35]1[NH:39][CH:38]=[N:37][N:36]=1)C.[C-]#N.[Na+].CS(C)=O>CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[C:33](=[O:32])[CH2:34][C:35]1[NH:36][N:37]=[CH:38][N:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reactant: CCOC(=O)Cc1nnc[nH]1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(N2CCN(C(=O)Cc3ncn[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Temperature: 25 °C
Yield: 0.7 %

Procedure:
A solution of (S)-5-(3-benzylpiperazin-1-yl)-8-methoxy-2-(trifluoromethyl)quinoline (Example 65, Compound 153) (100.0 mg, 0.25 mmol), (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester (83 mg, 0.50 mmol), sodium cyanide (24 mg, 0.50 mmol), and DMSO (2 mL). The reaction mixture was heated in a heat block at 100 C for 24 h then cooled to room temperature, diluted with EtOAc, and washed with water followed by brine. The organic portion was dried over MgSO4, filtered, evaporated and purified by silica gel flash chromatography to afford product as a colorless solid (0.9 mg, 0.7%). LC/MS (Method B) 3.32 min, [m/z=510.9].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([Cl:20])[CH:14]=2)=[C:7]([Cl:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[C:15]([Cl:20])[CH:14]=2)=[C:7]([Cl:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Cl)c2)c(Cl)c1C
Reactant: CC(C)C(=O)Cl
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(Cl)c2)c(Cl)c1C
Yield: 74.2 %

Procedure:
Methyl[3,5-dichloro-4-(4-amino-3-chlorophenoxy)phenyl] acetate (17 mg) was coupled with isobutyryl chloride (5.0 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:4), 15 mg (74%) of methyl(3,5-dichloro-4-[3-chloro-4-isobutyramidophenoxy]phenyl) acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 4 mg (27%) of 3,5-dichloro-4-(4-isobutyramido-3-trifluoromethylphenoxy)phenylacetic acid, m/z 416, 418.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]>C(O)(C)C>[OH:31][C:26]1([C:27]([F:30])([F:29])[F:28])[CH2:25][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2cccs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccs2)cc1
Yield: 39.7 %

Procedure:
To a mixture of the amidine of step 1 (2.0 g, 7.1 mmol) and sodium bicarbonate (1.2 g, 14.3 mmol) in isopropanol (200 ml), 3-bromo-1,1,1-trifluoroacetone 1.1 ml, 10.7 mmol) was added. After heating at 80–85° C. for 16 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (25.7 g) was purified by chromatography (silica gel, ethyl acetate/hexane 55/45) to give the 4,5-dihydro-imidazole (1.1 g, 38%) as a white solid: mp (DSC) 214° C. Anal. Calcld. for C15H13N2S2O3F3: C, 46.15, H, 3.36, N, 7.18, S, 16.43. Found: C, 46.09, H, 3.26, N, 7.07, S, 16.71.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.C[Si]([C:18]#[N:19])(C)C.[Si:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[O:36][CH3:37])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(OCC)(=O)C>ClCCl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>[Si:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:18]#[N:19])=[CH:30][C:29]=1[O:36][CH3:37])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: COc1cc(C=O)ccc1O[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
After adding 3.12 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 3.3 g of MS3A, 1.11 g of Yb(OTf)3 and 4.75 ml of trimethylsilyl cyanide to a solution of 5.0 g of 4-t-butyldimethylsilanyloxy-3-methoxybenzaldehyde [CAS No. 69404-94-0] in 98 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 23 hours. Next, 500 ml of ethyl acetate was added to the reaction mixture, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layers were combined and washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.45 g) as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:16]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c(C)c1

Procedure:
156.4 mg of the target compound (0.44 mmol, 53.7%) was obtained using 1-(2,4-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[N:11][C:12]2[CH:31]=[CH:30][C:15]([C:16]([NH:18][C:19]([NH:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:17])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>O1CCCC1.CO>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:18][C:19]([NH:21][NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[O:20])=[O:17])=[CH:30][CH:31]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=Nc2ccc(C(=O)NC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc(CNc2ccc(C(=O)NC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
tert-Butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]methylidene}amino)benzoyl]carbamoyl}hydrazinecarboxylate (778.5 mg, 1.800 mmol) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (18 ml) and anhydrous methanol (9 ml), and the mixture was cooled to 0° C. Sodium borohydride (68.1 mg, 1.80 mmol) was added and the mixture was stirred at room temperature for 30 min. Acetic acid (0.22 ml, 3.85 mmol) was added and the mixture was stirred for 15 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 40 g, dichloromethane:methanol=20:1→15:1). The pure fractions were concentrated under reduced pressure, ethyl acetate (30 ml) and tert-butyl methyl ether (10 ml) were added to the residue, and the resulting solid was collected by filtration and dried under reduced pressure to give tert-butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]methyl}amino)benzoyl]carbamoyl}hydrazinecarboxylate (653.1 mg, 1.503 mmol, yield 83.5%) as a white solid.