Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13])=[C:8]([F:25])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([OH:23])=[O:22])(=[O:13])=[O:14])=[C:8]([F:25])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(C2CCCC2)cc1F
Temperature: 80 °C
Yield: 103.1 %

Procedure:
To a solution of 139 (33.0 mg; 0.084 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous sodium hydroxide (7.5 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether. The aqueous layer was separated and acidified with aqueous hydrochloric acid (5 mL; 2N) then extracted with ethyl acetate (2×15 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as a brown solid (32 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:33])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:35][S:36](O)(=[O:38])=[O:37]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:33])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:36]([Cl:35])(=[O:38])=[O:37])=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)c1cccc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(C)c1cc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)ccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
To a mixture of 4-(3-isopropylphenoxyactamido)butyric acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 25, 4.8 g, 9.75 mmol) and 2 mL of CH2Cl2 was added drop-wise ClSO3H (3.3 mL, 5.8 g, 50 mmol) at 0° C. with vigorous stirring. The mixture was stirred at 0° C. for 40 min. and then was poured onto crushed ice with vigorous stirring resulting in a thick mass. This was extracted with CH2Cl2. The organic layers were dried, and concentrated under reduced pressure. The residual oil was passed through a short silica gel column to remove material that was not moving on TLC. The eluent was concentrated to give Intermediate 26 (3.3 g, 57%) as a light brown foam.
Reaction SMILES: [CH:1]1([C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+].O>CO>[CH:1]1([C:7]2[C:8]3[O:9][C:10]4[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:23](=[O:26])[C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1Oc1ccccc1C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2oc2c(C3CCCCC3)cccc12
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 18.4 g (65 mmol) of 2-(2-cyclohexylphenoxy)benzoic acid and 190 g of polyphosphoric acid is kept at 100° C. for 2 hours. The reaction mixture is then diluted with 200 ml of methanol, neutralized with sodium carbonate and poured onto about 800 ml of water. The product which has precipitated is filtered off, washed with water and dried under a high vacuum. 14.6 g (77% ) of 4-cyclohexylxanthone, melting point 122°-124° C., result as a beige powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1)[CH3:2].[OH-].[K+]>CCO>[CH2:1]([N:3]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)COc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 68.2 %

Procedure:
Methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenoxy)methyl]-benzoate (0.242 g, 0.536 mmol) was dissolved in EtOH (5 ml, 95%), potassium hydroxide (0.060 g, 1.072 mmol) was added. The reaction was performed in an single node microwave oven (7 min, 150° C.). Work-up was by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml) and the organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.160 g of 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenoxy)methyl]benzoic acid (yield 68.2%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][C:25]1[N:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27][CH:26]=1.O>COC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:29]2[CH:28]=[N:27][CH:26]=[C:25]([Cl:24])[N:30]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: CC1(C)OB(c2cncc(Cl)n2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cncc(Cl)n2)sc1C(=O)NCc1ccccc1
Reaction time: 72 h
Yield: 23.1 %

Procedure:
Part B. To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid benzylamide (350 mg, 1.13 mmol, 1.0 equiv) in dimethyl ether (4 mL) was added Na2CO3 (240 mg, 2.26 mmol, 2.0 equiv), 6-chloropyrazine-2-boronic acid pinacol ester (680 mg, 2.82 mmol, 2.5 equiv), PdCl2(dppf) (83 mg, 0.11 mmol, 0.1 equiv) and water (1 mL) in a sealed tube. The reaction was immersed in an oil bath preheated to 50° C. After 3 days, the reaction was cooled and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to give 2-(6-chloropyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (90 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.93 (s, 1H), 7.31-7.39 (m, 4H), 7.23-7.30 (m, 1H), 4.46 (d, J=8.0 Hz, 2H), 2.67 (s, 3H); MS (M+H)+=345.1, Rt=1.46 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:18]([O-])=O)[CH:14]=2)[N:9]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:8]1=[O:27].C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[C:8](=[O:27])[N:7]([CH2:6][C:5]1[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]2=[O:17]
Reactant: COc1ccc(Cn2c(=O)c3cc([N+](=O)[O-])ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3cc(N)ccc3n(C3CCOCC3)c2=O)cc1OC

Procedure:
A mixture of 1 g of the compound obtained in Step 6.3, 0.36 g of ammonium formate and 0.24 g of Pd/C (10%) in 10 ml of EtOH purged beforehand with nitrogen is irradiated in a microwave field for 10 minutes at 80° C. The resulting mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with an EtOAc/DCM mixture from (0/100, v/v) to (100/0, v/v) to give the expected product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)nc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A stirred suspension of methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate (D7, 1.0 g, 4.1 mmole) in dichloromethane (80 ml) was treated with pyridine (0.66 ml, 8.2 mmole), followed by 4-chlorobutyryl chloride (0.47 ml, 4.3 mmole). The resulting solution was stirred at 25° C. for 2 h, then treated with 5% Na2CO3 solution and after 30 minutes, the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a pale yellow solid. This was recrystallised from ethyl acetate/60-80 petrol to afford the title compound as a beige solid (1.13 g, 80%).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C[N+]1C=CN([S:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])C=1.Cl.[CH3:25][C:26]1[C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[S:29][C:30]=1[NH2:31]>CC#N>[CH3:25][C:26]1[C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[S:29][C:30]=1[NH:31][S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: C[n+]1ccn(S(=O)(=O)N2CCCCC2)c1
Reactant: Cc1c(N)sc2ccccc12
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: Cc1c(NS(=O)(=O)N2CCCCC2)sc2ccccc12
Temperature: 140 °C
Yield: 40 %

Procedure:
To a solution of compound 1-I (85.2 mg, 0.37 mmol) in MeCN (1.0 mL) was added a solution of compound 1-C (120.8 mg, 0.74 mmol) in MeCN (1.0 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 10 minutes. The reaction mixture was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 45% MeCN—H2O (0.1% TFA) to 65% MeCN—H2O (0.1% TFA) gradient to afford 46 mg of compound 1-J as a film. 1H-NMR (CDCl3, 400 MHz): δ 7.71-7.73 (t, 1H), 7.63-7.66 (t, 1H), 7.34-7.40 (m, 2H), 6.28 (s, 1H), 3.27-3.29 (m, 4H), 2.39 (s, 3H), 1.53-1.73 (m, 6H); MS (method 2): m/z 311.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:16])[C:11](O)=[O:12])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:31][O:32][C:33]1[C:34](=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:35][CH3:36].Cl>ClCCCl.[Fe](Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:40]=[C:39]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C@@H:10]([C:11]([C@@H:10]([N:14]2[C:15](=[O:16])[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:23]2=[O:24])[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:38]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[C:34]([O:35][CH3:36])[CH:37]=2)=[O:12])[N:14]2[C:15](=[O:16])[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:23]2=[O:24])[CH:38]=[CH:37][C:34]=1[O:35][CH3:36]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C[C@@H](C(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(C(c2ccc(OC)c(OC)c2)[C@@H](C(=O)[C@H](C(c2ccc(OC)cc2)c2ccc(OC)c(OC)c2)N2C(=O)c3ccccc3C2=O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A solution of 3.25 g (10.0 mmole) N-phthaloyl-0-methyl-(S)-tyrosine in 50 ml 1,2-dichloroethane was combined with 2.29 g (11.0 mmole) phosphorus pentachloride at 0° C. and agitated at first for 30 minutes at 0° C. and then for 16 hours at room temperature. After the addition of another 50 ml 1,2-dichloroethane, a tenth of the solution was rapidly added to an agitated solution of 1.38 g (10.0 mmole) catechol dimethylether and 160 mg iron-(III)-chloride (10 mole percent) in 70 ml 1,2-dichloroethane. The reaction mixture was heated to 50° C. and the remaining solution of acid chloride was added dropwise in a continuous manner over 12 hours. The mixture was agitated 12 hours further at 50° C. and then cooled down to 0° C. 100 ml 1N hydrochloric acid cooled down to 0° C. were added and the mixture was agitated for 24 hours at room temperature. The aqueous phase was separated off and extracted twice with 40 ml methylene chloride per extraction. The combined organic phases were washed with 150 ml saturated, aqueous sodium hydrogen carbonate solution, then with 100 ml water, and dried over sodium sulfate. After removal of the solvent at 40° C. under reduced pressure, the raw product was chromatographed over a silica gel column. 1.93 g (43 % of theory) (S)-3,4-dimethoxyphenyl-[2-(4-methoxyphenyl)-1-phthalimidoethyl]-ketone of reagent purity were obtained as oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[NH2:27][C:28]1[CH:29]=[C:30]([C:34]2[N:35]=[CH:36][NH:37][CH:38]=2)[CH:31]=[CH:32][CH:33]=1.Cl.C(N(CC)CC)C.N1CCCCC1>CN(C=O)C.O>[NH:37]1[CH:38]=[C:34]([C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[NH:27]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:35]=[CH:36]1
Reactant: Nc1cccc(-c2c[nH]cn2)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1cccc(-c2c[nH]cn2)c1)c1ccccc1

Procedure:
Prepared by reacting 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone with 1.5 equivalents of 4-(3-amino-phenyl)-imidazole×2 HCl and 3.25 equivalents of triethylamine in DMF (100° C., for 1.5 hours), subsequent treatment with 5 equivalents of piperidine (20° C., 1 hour) and precipitation with water.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].[C:10]([O-])([O-])=O.[K+].[K+].IC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1ncc(Cl)c(Cl)c1=O
Temperature: 115 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
25 g (151 mmoles) of 4,5-dichloropyridazinone are placed in a stainless steel reactor in the presence of 25.13 g (181 mmoles) K2CO3, 1 g (3.03 mmoles) of tetrabutylammonium bromide and 14.2 mL (227 mmoles) of iodomethane in 150 mL acetonitrile. The reaction medium is agitated for 4 h at 115° C. then filtered. The filtrate is concentrated to dryness then solubilized in AcOEt and washed in acid water (pH 1), then with NaCl-saturated water. After drying over Na2SO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2). 19.1 g of intermediate 3a are thus obtained in the form of a yellow solid (yield 70%). TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 70:30, Rf=0.48.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:17][CH2:18]O>>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Cl)c1F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cccc(Cl)c1F
Yield: 79.3 %

Procedure:
A solution of 2-(3-chloro-2-fluorophenyl)acetic acid (2.56 g, 13.6 mmol) and thionyl chloride (100 mL, 1371 mmol) was stirred at 95° C. for 2 hours in a 250 mL round bottom flask. The solution was concentrated, azeotroped in toluene, and dried in vacuo to give the crude acid chloride, which was then stirred in EtOH (150 mL, 2576 mmol) at 25° C. for 16 hours. The solution was concentrated in vacuo, diluted with saturated NaHCO3 (aq) (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated NaHCO3 (aq) (100 mL), with water (100 mL), and then with brine (75 mL). The organic layer was dried over MgSO4, concentrated, and purified by silica flash column chromatography (0-10% EtOAc in hexane) to give ethyl 2-(3-chloro-2-fluorophenyl)acetate (2.335 g, 79.4% yield). MS m/e=217 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16]C#N)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].O.C(P(CC)CC)C>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Agent: CCP(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 86.9 %

Procedure:
3,5-bis(1,1-Dimethylethyl)-4-hydroxyphenyl thiocyanate (55 g, 0.209 mole) was dissolved in acetone (200 ml) under an argon atmosphere. Water (7.6 g, 0.42 mole) was added and the reaction cooled to 0° C. Triethylphosphine (24.7 g, 0.209 mole) was added dropwise over a period of 1 hour and the reaction was then allowed to warm to room temperature with stirring. The solution was concentrated, solvents removed, and the resulting oil purified by chromatography on silica. The fractions containing the thiol were combined, the solvents removed to yield a white powder which was recrystallized from methanol/water and dried to yield 43.3 g of the desired product. NMR confirmed the identity of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:5][O:6][CH2:7][CH2:8][N:9]=[N+]=[N-].C(N(CC)CC)C.C(O)CCO.[BH4-].[Na+]>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:5][O:6][CH2:7][CH2:8][NH2:9]
Reactant: Cc1ccc(COCCN=[N+]=[N-])cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: OCCCO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(COCCN)cc1C
Yield: 74.2 %

Procedure:
2.29 g (11.2 mmol) of 2-(3,4-dimethylbenzyloxy)ethylazide obtained in step 2 was dissolved in 15 ml of isopropanol while stirring, and 3.1 ml (22 mmol) of triethylamine was added thereto. The mixture was added to an isopropanol solution containing 1.1 ml (11 mmol) of 1,3-propanediol and then 4.22 g (0.11 moles) of NaBH4 was added thereto. The mixture was stirred at an ambient temperature for 1 hour and the solvent was distilled off under a reduced pressure. The residue was dissolved in 10% aqueous citric acid and the resulting solution was washed three times with 30 ml of ether: hexane (1:1). The pH of the aqueous layer was adjusted to 12 with a 6N sodium hydroxide solution and then a saturated sodium chloride solution was added thereto. Thee aqueous layer was extracted with 30 ml of dichloromethane 3 times. The organic layer was dried and the solvent was evaporated under a reduced pressure to obtain 1.49 g (yield 75%) of the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+]>[Pd].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(O)C.O>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([C:2]2[CH:7]=[CH:6][C:5]([O:13][CH3:10])=[CH:4][CH:3]=2)[CH:2]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(OC)c2)cc1
Reaction time: 15 h
Yield: 185.7 %

Procedure:
A mixture of a mixed solvent (toluene/ethanol/water=1.5/1.5/1; 900 ml), the compound (T-2) (48.6 g, 319.6 mmol), 1-iodo-4-methoxybenzene (68.0 g, 290.6 mmol), 5% palladium on carbon (3.40 g), potassium carbonate (60.2 g, 435.9 mmol) and tetrabutylammonium bromide (23.4 g, 72.7 mmol) was refluxed with stirring for 15 hours under an atmosphere of nitrogen. The resulting reaction mixture was extracted with toluene (400 mL) three times, and the organic layers were washed with water. After the organic layer had been dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: toluene), and then by recrystallization from a mixed solvent of heptane, methanol and ethyl acetate to give colorless crystals (57.8 g) of 3,4′-dimethoxybiphenyl (T-3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:44][C:41]1[CH:40]=[CH:39][C:38]([CH:31]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)[N:32]2[CH2:33][CH2:34][N:35]([CH2:22][CH2:21][CH2:20][C:11]3[CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=3)[CH2:36][CH2:37]2)=[CH:43][CH:42]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
127 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (75 mg, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[C:18]([CH3:23])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1C
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (26 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 70 mg (yield 95%) of the title compound.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)=[C:8]([CH:12]=1)[C:9](N)=[O:10].Cl.S(Cl)([Cl:23])=O.C(N(CC)CC)C>O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH:14]([CH2:18][CH2:17][Cl:23])[CH2:15][N:16]([CH3:19])[C:9](=[O:10])[C:8]=2[CH:12]=1
Reactant: CN1CCC(Oc2ccc(Br)cc2C(N)=O)C1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CC(CCCl)Oc2ccc(Br)cc2C1=O
Temperature: 15 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of 9.6 g (0.24 mole) of sodium hydroxide in 200 ml of water was added 37 g (0.12 mole) of 5-bromo-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture was heated at reflux for 18 hr. The pH of the mixture was adjusted to 6.7 with concentrated hydrochloric acid solution. The solution was concentrated under reduced pressure and the residue was boiled in 250 ml of isopropyl alcohol for 1 hr. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in chloroform and to the solution was added 28.3 g (0.24 mole) of thionyl chloride. The mixture was heated at reflux for 0.5 hr and cooled to 15° C. with an ice bath. To the mixture was added dropwise 26.6 g (0.26 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The reaction mixture was stirred at room temperature for 1 hr, then washed consecutively with 3N hydrochloric acid, 15% aqueous sodium hydroxide and water. The chloroform layer was dried over magnesium sulfate and concentrated under reduced pressure to give 23 g (60%) of brown solid. A portion of the solid was recrystallized from ethyl acetate-isopropyl ether, m.p. 92°-94° C.