Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([F:30])[CH:24]=1.C([O-])(=O)C.[K+]>CS(C)=O>[CH2:20]([N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([F:30])[CH:24]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH2:1][CH3:2])[CH3:21]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCN(CC)Cc1cc(-c2ccn3ccnc3c2)ccn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(CC)Cc1cc(-c2ccn3c(-c4ccc(N)c(F)c4)cnc3c2)ccn1
Temperature: 100 °C
Reaction time: 14 h
Yield: 20.6 %

Procedure:
Combine diethyl-(4-imidazo[1,2-a]pyridin-7-yl-pyridin-2-ylmethyl)-amine (1.00 g, 3.57 mmol), 4-bromo-2-fluoro-phenylamine (1.36 g, 7.13 mmol) and potassium acetate (0.700 g, 7.13 mmol) in DMSO (4 mL). De-gas the mixture for 10 minutes with N2. Add dichlorobis(triphenylphosphine) palladium (II) (0.250 g, 0.357 mmol); stir the reaction mixture for 14 hours under N2 at 100° C. Purify using an SCX cartridge (10 g VARIAN bond elut), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in methanol:dichloromethane. Purify via reverse phase chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03% HCl H2O (5:95) to 100% MeCN; 30 min). Compound obtained is partitioned between ethyl acetate and 1 N NaOH. Wash the organic layer with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate to afford the title compound (0.286 g, 21%). MS(ES), m/z 390 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(-c2ccc(C)cc2N)cc1
Product: CC(=O)Nc1ccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (0.041 g, 0.23 mmol) was reacted with the product from Example 215b (0.062 g, 0.23 mmol) for 46 h at 100° C. following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.073 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.98 (s, 3 H) 2.42 (s, 3 H) 2.72 (s, 3 H) 6.28 (d, J=6.99 Hz, 1 H) 7.27-7.56 (m, 7 H) 7.74 (d, J=8.46 Hz, 1 H) 8.33 (d, J=7.35 Hz, 1 H) 8.94 (d, J=8.82 Hz, 1 H) 9.95 (s, 1 H) 11.06 (s, 1 H); MS (ESI+) m/z 383.1 (M+H)+, (ESI−) m/z 381.1 (M−H)−.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[OH:19])[CH:14]=[O:15].N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[O:19][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:14]=[O:15]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc(C=O)cc(Cl)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To a flask containing of dichloromethane (58 ml) was added powdered 4 A sieves (3.37 g, activated at 500° C. for 8 h), phenylboronic acid (3.53 g, 28.95 mmol), 3-chloro-4-hydroxy-5-methoxybenzaldehyde (1.08 g, 5.79 mmol), copper (II) acetate (1.05 g, 5.79 mmol), pyridine (2.33 ml, 28.95 mmol) and triethylamine (4.0 ml, 28.95 mmol). The reaction flask was fitted with a drying tube and stirred overnight at room temperature. Filtration through celite and removal of volatiles in vacuo followed by column chromatography (silica, 10% ethyl acetate in hexane) provided the title compound as a yellow solid (540 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 7.28 (t, j=8.0 Hz, 2H), 7.05 (t, j=7.2 Hz, 1H), 6.83 (d, j=8.4 Hz, 2H), 3.84 (s, 3H). M+1=263
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH:14](=[N:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]([O:25][CH3:26])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:39][CH2:40]Br>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[Cl:39][CH2:40][C:22]([N:21]=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: ClCBr
Reactant: COC(=O)C(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CCl)(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of lithium diisopropylamide (10 mmol) prepared in situ from a solution of 1N diisoproppylamine in tetrahydrofuran (THF) and a solution of butyl lithium (2N) in hexane and hexamethylphosphoramide (HMPA) (2.5 ml) in THF cooled to -78° C., magnetically stirred, and kept under nitrogen, is added slowly a solution of methyl 2,6-bis(benzylideneamino)hexanoate (3.365 g, 10 mmol) in dry THF (20 ml). The reaction mixture is stirred at -78° C. for 1/2 hour, and then a solution of chlorobromomethane (1.3 g, about 10 mmol) in dry THF (10 ml) is added rapidly. The temperature is allowed to rise slowly to room temperature, and the stirring is continued overnight. The reaction mixture is quenched with water and extracted with ether. The ether extract is washed with water and concentrated at reduced pressure to give methyl 2-chloromethyl-2,6-bis(benzylideneamino)hexanoate as an oily residue.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([O:13][CH3:14])[CH:7]=[C:6]([F:15])[C:3]=1[CH:4]=[O:5].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][OH:28]>>[CH3:27][O:28][CH:4]([O:5][CH3:16])[C:3]1[C:2]([F:1])=[C:9]([N+:10]([O-:12])=[O:11])[C:8]([O:13][CH3:14])=[CH:7][C:6]=1[F:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(F)c(C=O)c(F)c1[N+](=O)[O-]
Reactant: CO
Product: COc1cc(F)c(C(OC)OC)c(F)c1[N+](=O)[O-]
Yield: 85 %

Procedure:
A mixture of 2,6-difluoro-4-methoxy-3-nitro-benzaldehyde (6.3 g, 29 mmol) in methanol (30 mL) with p-toluenesulfonic acid (110 mg, 0.58 mmol) was heated at reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a pale yellow solid (6.52 g, 85%). 1H NMR (CDCl3) 6.59 (1 H, dd, J=11.48, 2.08 Hz), 5.52 (1 H, s), 3.93 (3 H, s), 3.45 (6 H, s).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([NH:23][C:24]1[S:28][C:27]2[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=2[C:25]=1[C:33]([NH2:35])=[O:34])=[O:22]>CN(C=O)C.CO>[OH:10][CH2:9][CH2:8][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][N:5]([CH2:20][C:21]([NH:23][C:24]2[S:28][C:27]3[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=3[C:25]=2[C:33]([NH2:35])=[O:34])=[O:22])[CH:6]=1
Reactant: OCCc1c[nH]nc1C(F)(F)F
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cn2cc(CCO)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 60 °C
Yield: 40 %

Procedure:
To a solution of 2-(3-trifluoromethylpyrazol-4-yl)-ethanol (18 mg, 0.1 mmol) in DMF (0.5 mL) was added potassium carbonate (16 mg, 0.12 mmol). The reaction mixture was stirred at 60° C. for 25 min before 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (32 mg, 0.1 mmol) was added. Heating at 60° C. was maintained for 4 h before the reaction mixture was allowed to cool to RT. The whole was diluted with MeOH (0.5 mL), and filtered before being purified by preparative reverse phase HPLC to give the desired product as a white solid (17 mg, 0.04 mmol, 41%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N+:16]([C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=O)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[N+:16]([C:19]1[CH:20]=[CH:21][CH:22]2[CH:27]([CH:28]=1)[C:26]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:25][CH2:24][CH2:23]2)([O-:18])=[O:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: O=[N+]([O-])C1=CC2C(OS(=O)(=O)C(F)(F)F)=CCCC2C=C1
Reaction time: 24 h

Procedure:
9.8 ml of trifluoromethanesulphonic anhydride are poured at 0° C. into a solution of 10 g of 7-nitrotetralone and 11.8 g of 2,6-di-tert-butyl-4-methylpyridine in 365 ml of dichloromethane. After 24 hours at ambient temperature, concentration to dryness and taking up the residue in 200 ml of pentane at reflux for 30 minutes, the precipitate formed is filtered off. The organic phase is washed with a 1N hydrochloric acid solution and then with water, dried over magnesium sulphate and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[N:9][CH:8]=[C:7]([Br:18])[CH:6]=2.[CH2:19]([O:21][CH2:22][C:23]([Cl:25])=[O:24])[CH3:20]>C(#N)C>[ClH:25].[Br:18][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([NH:12][CH2:13][C:14]([OH:16])([CH3:15])[CH3:17])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][O:21][CH2:19][CH3:20])[CH:3]=[N:4]2)=[N:9][CH:8]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)cnc12
Solvent: CC#N
Product: CCOCC(=O)Nc1cnc2cc(Br)cnc2c1NCC(C)(C)O
Product: Cl
Reaction time: 0.08 h
Yield: 81.1 %

Procedure:
A mixture of 1-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (100.0 g, 321.4 mmol) and acetonitrile (1 L) was stirred for five minutes, and ethoxyacetyl chloride (43.3 g, 353.3 mmol) was added. The reaction was stirred overnight at room temperature. The solid product was isolated by filtration and washed with acetonitrile (200 mL) to provide 113 g of N-{7-bromo-4-[(2-hydroxy-2-methylpropyl)amino][1,5]naphthyridin-3-yl}-2-ethoxyacetamide hydrochloride as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.P(Cl)(Cl)(Cl)=O.CN([CH:22]=[O:23])C.Cl([O-])=[O:25].[Na+].P([O-])(O)(O)=O.[Na+]>O1CCOCC1>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:22]([OH:23])=[O:25]
Reactant: [O-][Cl+][O-]
Reactant: CN(C)C=O
Reactant: FC(F)Oc1ccc2[nH]ccc2c1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=C(O)c1c[nH]c2ccc(OC(F)F)cc12

Procedure:
5-Difluoromethoxyindole (PCT 2007/096395) was formylated at the 3-position using the Vilsmeyer-Haack protocol (phosphorous oxychloride/DMF). The resulting aldehyde was oxidized with sodium chlorite/sodium dihydrogen phosphate in aqueous dioxane. MS (m/e) 227.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.F[B-](F)(F)F.[N:16]1([O:25][C:26](N(C)C)=[N+](C)C)[C:20]2C=CC=CC=2N=N1.CNOC>C(N(CC)C(C)C)(C)C.CN(C)C=O>[Br:1][C:2]1[C:3]([C:8]([N:16]([O:25][CH3:26])[CH3:20])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(C(=O)O)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nn(C)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (2.04 g, 10 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.21 g, 10 mmol), N,O-dimethylhydroxylamine (1.22 g, 20 mmol) in N,N-Diisopropylethylamine (5 mL) and N,N-Dimethylformamide (20 mL) was stirred for 12 h at room temperature. The mixture was concentrated in vacuum, and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give the titled product as a colorless oil (2.4 g, 97%). LC/MS m/z 247 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][CH2:32][C:31]([CH2:36]C)([CH2:34]C)[CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:34][C:31]1([CH3:36])[CH2:30][CH2:29][CH:28]([C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:33][CH2:32]1
Reactant: CCC1(CC)CCC(c2cc(N3CCC[C@H](OC)C3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CCCN(c2ccc(N3CCNCC3)c(C3CCC(C)(C)CC3)c2)C1
Reaction time: 0.33 h

Procedure:
(S)-4-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylic acid t-butyl ester (59 mg, 0.1148 mmol) produced in Example (50b) was dissolved in a mixed solvent of dichloromethane (0.7 mL)-water (1 drop). Trifluoroacetic acid (0.177 mL, 2.296 mmol) was added thereto followed by stirring for 15 hours and 20 minutes under the same conditions. Aqueous solution of potassium carbonate was added to the reaction mixture to make the mixture basic. The mixture was then extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure to give a crude product of (S)-1-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine as a brown oil. This was directly used without purification for the following reaction.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>>[C:6]1([C:8]#[C:9][CH:24]([C:23]2[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:22]=2[O:21][CH3:20])[OH:25])[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1ccc(C(O)C#Cc2ccccc2)c(OC)c1OC
Yield: 99 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,3,4-trimethoxybenzaldehyde (1.00 g, 5.10 mmol) was reacted to give the title compound (1.50 g, 99%). 1H NMR (400 MHz, DMSO-d6): δ 7.45-7.28 (m, 6H), 6.88-6.83 (m, 1H), 5.97-5.92 (d, 1H), 5.73-5.68 (d, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: C(O)(=O)C.O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:29]([F:32])([F:31])[F:30])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([N+:25]([O-])=O)[CH:24]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1>[Fe].C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:29]([F:30])([F:32])[F:31])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([CH:24]=3)[NH2:25])[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Temperature: 75 °C
Reaction time: 0.83 h
Yield: 64.9 %

Procedure:
An iron powder (3.46 g) was added to a mixture of acetic acid (0.38 g), water (15 ml) and ethanol (30 mL) at room temperature, and thereto was added 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-chloronitrobenzene (2.73 g) obtained by Reference Production Example 19 at 75° C. After stirring at 75° C. for 50 minutes, the reaction mixture was filtrated and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-chloroaniline (1.65 g).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C)C=O>O>[CH2:41]([O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (165 mg), benzyl bromide (205 mg), and N,N-dimethylformamide (10 ml) was stirred at 80° C. for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (385 mg, yield: 64%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][OH:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].[H][H].[CH3:24]I>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][O:19][CH3:24])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CI
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.7 %

Procedure:
To a solution of the title compound of Step A (400 mg, 1.34 mmol) in dry dimethylformamide (13 mL) at 0° C. under nitrogen was added NaH (60% dispersion in mineral oil, 134 mg, 3.3 mmol). After stirring for 30 minutes at 0° C. until hydrogen evolution ceased, methyl iodide (949 mg, 6.61 mmol) was added. The reaction mixture was warmed to room temperature and stirred for about 19 hours. The solution was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with 1M HCl (3×100 ml), brine (100 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (30% hexane in dichloromethane) to afford the title compound (410 mg). NMR (400 MHz, CDCl3) δ7.36 (s, 2H), 6.75-6.83 (m, 4H), 4.40 (s, 2H), 3.75 (s, 3H), 3.43 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:24][C:25](=[O:27])[CH3:26])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:24][C:25](=[O:27])[CH3:26])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: [H][H]
Reactant: CC(=O)OC(C#CCOC1CCCCO1)COc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCOC1CCCCO1)COc1cccc(C(F)(F)F)c1

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-(3-trifluoromethylphenoxy)-2-pentyne (40.18 g.; 0.104 mole) is dissolved in ethyl acetate (200 ml.). 5% Palladium on carbon (5 g.) is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 45 lbs./in2 and 25°. When 0.208 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil, yield 40.60 g.; pmr (CDCl3) δ 2.13 (3H, s CH3COO), 4.10 (2H, d CH2O), 5.20 (1H, m CHOCO), 7.22 (4H, m Aryl H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[O:7]=[C:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[C:3](=[O:12])[N:2]1[O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A mixture of N-hydroxyphthalimide (10 g, 61.3 mmol), K2CO3 (16.9 g, 122 mmol) and tert-butyl bromoacetate (12 g, 9 mL, 61.3 mmol) in DMF (60 mL) was stirred at room temperature for 3 hours and the solvent was evaporated under high vacuum. The residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 and filtered. The residue after evaporation of the solvent was recrystallized from a mixture of CH2Cl2/EtOAc/hexane to give the title compound (12 g, 71% yield) as a white solid. Mp 140-141° C. 1H NMR (300 MHz, CDCl3) δ 7.80-7.90 (m, 2H), 7.74-7.77 (m, 2H), 4.71 (s, 2H), 1.49 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 166.0, 163.0, 134.7, 128.9, 123.7, 83.0, 73.5, 28.1. Mass spectrum (API-TIS) m/z 278 (MH+), 295 (MNH4+). Anal. calcd. for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.47; H, 5.31; N, 4.96.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][N:23]([CH3:27])[C:24](Cl)=[O:25].N1C=CC=CC=1.[Cl-].[NH+]1C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:16][C:24](=[O:25])[N:23]([O:22][CH3:21])[CH3:27])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCOc2ccc(N)cc2)cc1
Reactant: CON(C)C(=O)Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc(C(C)(C)C)cc2)cc1
Yield: 26.1 %

Procedure:
A mixture of 26.9 g of 4-(4-tert-butylphenethyloxy)aniline, 13 g of N-methoxy-N-methylcarbamyl chloride, 10 ml of pyridine and 300 ml of toluene is heated under reflux for 7 hours. Thereafter, water is added to dissolve pyridinium chloride, and the separated toluene layer is washed with dilute hydrochloric acid, thoroughly washed with water and dried over anhydrous sodium sulfate. The solvent is then removed under reduced pressure, and the crude crystals obtained are repeatedly recrystallized from ethanol to obtain 9.3 g of N'-[4-(4-tert-butylphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 14°-15° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2.[CH3:16][S:17](Cl)(=[O:19])=[O:18].N1C=CC=CC=1.Cl>C(Cl)Cl.O>[CH3:16][S:17]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=1)(=[O:19])=[O:18]
Reactant: OCCOCCc1ccc2sccc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCc1ccc2sccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In 20 mL of methylene chloride is dissolved 2.10 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-ethanol. At an ice-cooled temperature, 1.63 g of methanesulfonyl chloride and 1.47 g of pyridine are added to the solution obtained above, and the mixture thus formed is stirred at the same temperature as above for 30 minutes and then at ambient temperature for 12 hours. Then, methylene chloride and water are added to the reaction mixture, pH is adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: n-hexane:ethyl acetate=4:1 to 2:1) to obtain 2.50 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-ethyl methanesulfonate.