Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH3:12])([CH3:11])[N:10]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:19]([C:18]2[CH:21]=[CH:22][C:15]([N:14]([CH3:23])[CH3:13])=[CH:16][CH:17]=2)[O:20][C:9]([CH3:11])([CH3:12])[N:10]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC1(C)N=C1c1ccccc1Cl
Product: CN(C)c1ccc(C2OC(C)(C)N=C2c2ccccc2Cl)cc1

Procedure:
According to the procedure described in Example 1, from 30 g of 3-(o-chlorophenyl)-2,2-dimethyl-2H-azirine and 24 g of p-(dimethylamino)benzaldehyde there was obtained 4-(o-chlorophenyl)-5-[p-(dimethylamino)phenyl]-2,2-dimethyl-3-oxazoline which melted at 72.5°-73.5° C. after drying for 4 hours at 35° C. and 13 Torr.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:15][C:14]=3[C:25]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([C:30]([OH:29])=[O:38])=[CH:32][CH:33]=3)=[O:26])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1nc(-c2ccccc2F)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)c1ccc(NC(=O)c2nc(-c3ccccc3F)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid (Example 50) was reacted with 4-amino-benzoic acid methyl ester according to the procedure of Example 20, step d. Deprotection was carried out using essentially the same procedure as in Example 36, step d to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:38]=[CH:37][C:23]([CH2:24][O:25][C:26](SC2N=C(C)C=C(C)N=2)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].[OH-].[Na+]>O.O1CCOCC1>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])=[O:27])=[CH:37][CH:38]=1)([O-:19])=[O:18]
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.55 g of trans-4-hydroxyl-L-proline and 7.5 ml of triethylamine were dissolved in 15 ml of water, and a solution of 15.95 g of S-p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 35 ml of dioxane was added thereto dropwise. The resulting mixture was stirred at room temperature for 1.5 hours and allowed to stand overnight. To the reaction mixture was added 30 ml of a 2N sodium hydroxide aqueous solution under ice-cooling, and the resulting mixture was extracted with diethyl ether. The ethereal layer was washed with 20 ml of a 1N sodium hydroxide aqueous solution and combined with the alkaline aqueous layer. The combined mixture was made acidic with 100 ml of a 2N hydrochloric acid aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a 2N aqueous solution of hydrochloric acid, dried over sodium sulfate and distilled off to remove the solvent. The resulting crude crystals were washed with warm ethyl acetate to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:6]=1)C.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[Cl:11][C:10]1[C:5]([C:4]([OH:32])=[O:3])=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:8]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:9]=1
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)c(OCc2ccc(OC)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(COc2cc(Cl)c(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Yield: 91.3 %

Procedure:
A solution of 6-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid ethyl ester (110 g: 240 mMol.) in a mixture of ethanol (800 ml), pg,64 tetrahydrofuran (150 ml), and aqueous 2N -sodium hydroxide (264 ml: 2.2 Eq.) is heated at 70° C. for 2 hours. The reaction mixture is cooled and acidified with hydrochloric acid. The resulting precipitate is collected by filtration and washed with ethanol and water to give 6-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (94 g). Yield: 99%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28]O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.CN(C=O)C.S(Cl)([Cl:37])=O>>[Cl:37][CH2:28][CH2:27][O:26][C:25]1[C:18]2[C:19](=[N:20][CH:21]=[N:22][C:17]=2[NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)=[C:2]([CH3:1])[CH:3]=2)[NH:23][N:24]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCO)c34)cc2C)cn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Yield: 84 %

Procedure:
2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethanol (prepared as described in Example 8/1.7 g, 4.33 mmol) was dissolved in thionyl chloride (10 ml) and DMF (100 μL) was added. The mixture was refluxed for 2 hours and then the volatiles were removed under reduced pressure. The residue was triturated with a saturated solution of sodium bicarbonate and the solid filtered and washed with ether to provide the title compound (1.5 g, 84%); NMR Spectrum: 2.20 (s, 3H), 2.44 (s, 3H), 4.09 (t, 2H), 4.60 (t, 2H), 6.96 (d, 1H), 7.18-7.25 (m, 2H), 7.60 (d, 1H), 7.67 (s, 1H), 8.17 (s, 1H), 8.31 (s, 1H), 8.34 (br s, 1H); Mass Spectrum: 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](Cl)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:19]([C:15]3[C:16]4[C:11](=[CH:10][C:9]([O:8][C:4]5[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=5)=[CH:18][CH:17]=4)[CH:12]=[CH:13][CH:14]=3)=[O:20])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3cccc4cc(Oc5cc(Cl)ncn5)ccc34)cc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 2.2 mMol 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (Step 19.3) in 15 ml CH2Cl2 is added to a stirred solution of 410 mg (2.0 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 680 μl (4.0 mMol) diisopropylethylamine in 15 ml CH2Cl2. After 30 min, the reaction mixture is poured into a mixture of NaHCO3 and CH2Cl2. The aq. phase is separated off and extracted with CH2Cl2. The combined organic layers are washed with water and brine, dried (Na2SO4) and concentrated to give the crude product which is purified by column chromatography (SiO2; CH2Cl2/EtOH/NH3 95:4.5:0.5) to afford the title compound as a yellow powder.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@@H:6]1[C:17](O)=O)(=O)C.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>Cl>[C:20]([C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:17]([C@@H:6]3[C@H:5]([OH:4])[CH2:9][CH2:8][NH:7]3)=[N:31][C:26]=2[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Agent: Cl
Product: CC(C)(C)c1ccc2[nH]c([C@H]3NCC[C@H]3O)nc2c1
Temperature: 60 °C

Procedure:
The title compound was prepared according to Method 4 Steps 1 and 2 using (3R)-3-acetoxy-1-(tert-butoxycarbonyl)-L-proline (Preparation 47) and 4-tert-butyl-1,2-diaminobenzene. The residue was dissolved in 6N HCl (5 mL) at 0° C. and then heated to 60° C. for 4 hours. The reaction was cooled, concentrated in vacuo and purified through an SCX cartridge (47 mg, 66%).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35]N)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:33]4[CH:32]=[CH:31][C:30]5[O:25][CH2:26][CH2:27][O:28][C:29]=5[CH:34]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2
Yield: 33 %

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for Example 91 in 33% yield. MS: M=439.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl.O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[O:13][CH:11]([CH3:12])[CH2:10]2
Reactant: COc1ccc(CC(C)O)cc1Br
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1Br)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
18.04 g (132.4 mmol) of freshly melted zinc chloride is added to a solution of 32.46 g (132.4 mmol) of 1-(3-bromo-4-methoxyphenyl)-propan-2-ol and 20.01 g (132.4 mmol) of 4-nitrobenzaldehyde in 166 ml of dry benzene, and then dry hydrogen chloride gas is introduced for 3 hours. The reaction mixture is then heated to boiling for 1 hour and stirred with 150 ml of water. The organic phase is separated and washed in succession with water (2×50 ml), 20% sodium hydrogen sulfite solution (100 ml), 8% sodium bicarbonate solution (50 ml) and water (2×50 ml) and dried. After concentration by evaporation, a thick oil, which during treatment with hot ethanol (450 ml) yields crystalline 6-bromo-3-methyl-7-methoxy-1-(4-nitrophenyl)-isochroman, is obtained: 20.39 g (41%), melting point 128-129° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.Br[CH:16]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:21]
Reactant: CCOC(=O)C(Br)c1cccc2ccccc12
Reactant: Oc1ccccc1-n1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Oc1ccccc1-n1cccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Sodium hydride (90 mg, 3.9 mmol) was added to a solution of 1-(2-hydroxyphenyl)pyrrole (0.4 g, 2.5 mmol) in anhydrous THF (5 mL) at rt. The reaction mixture was stirred for 1 h at rt, and then a solution of ethyl α-bromo-α-(1-naphtyl)acetate (1.0 g, 4.0 mmol) in anhydrous THF (5 mL) was added dropwise. After 12 h at rt, the solvent was removed in vacuo, and the residue was taken up in dichloromethane. The organic layers were washed with brine, dried, and evaporated. The residue was purified by chromatography (toluene) to give 0.46 g of the title compound as a colorless oil; IR (neat): 1734 cm−1; 1H NMR (CDCl3) δ 1.10 (t, 3 H, J=7.0 Hz), 4.10 (m, 2 H,), 6.15 (s, 1 H), 6.30 (m, 2 H), 6.35-8.25 (m, 13 H).
Reaction SMILES: C(O)(C)C.C[O-].[Na+].[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH2:13]1[CH2:18][CH2:17][C:16](=[C:9]2[CH:8]=[CH:12][CH:11]=[CH:10]2)[CH2:15][CH2:14]1
Reactant: C1=CCC=C1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: C1=CC(=C2CCCCC2)C=C1

Procedure:
To a flask containing isopropyl alcohol (500 ml) and 25% sodiummethylate solution (10 g) are added a mixture of cyclopentadiene (150 g) and cyclohexanone (200 g) over a period of two hours. When addition is complete, the mixture is mixed with water and the organic layer extracted into hexane.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[OH:27][C:7]1[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:9]2[S:18][N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccncc2)c2snc(-c3ccccc3)c2c1O
Product: O=C(O)CNC(=O)c1nc(-c2ccncc2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-hydroxy-3-phenyl-7-pyridin-4-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 407.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:12][S:11][CH2:10][C:4]=2[S:5][C:6]=1C(O)=O.Cl>N1C2C(=CC=CC=2)C=CC1=O>[F:1][C:2]1[C:3]2[CH2:12][S:11][CH2:10][C:4]=2[S:5][CH:6]=1
Reactant: O=C(O)c1sc2c(c1F)CSC2
Agent: Cl
Agent: O=c1ccc2ccccc2[nH]1
Product: Fc1csc2c1CSC2
Temperature: 220 °C
Yield: 90 %

Procedure:
500 mg compound 6 from the previous step was mixed with 100 mg Cu powder and 20 ml quinolone. The mixture was heated at about 220° C. for about 2 hours. After cooling to about room temperature, the mixture was poured into 6 M HCl and extracted by ether 3 times. Compound 7 was dried by anhydrous Na2SO4. The yield was about 90%.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)[CH:12]=[CH:11][N:5]2[C:6](=[O:10])[C:7]=1[CH:8]=O.CN(C)C=O.[C:30]([O:34][C:35]([CH:37]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>O1CCCC1>[OH:1][C:2]1[N:3]=[C:4]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)[CH:12]=[CH:11][N:5]2[C:6](=[O:10])[C:7]=1/[CH:8]=[CH:37]/[C:35]([O:34][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:36]
Reactant: CC(C)c1csc(COc2ccn3c(=O)c(C=O)c(O)nc3c2)n1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Temperature: 100 °C
Yield: 62.4 %

Procedure:
2-Hydroxy-8-[(4-isopropyl-1,3-thiazol-2-yl)methoxy]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carbaldehyde (45 mg, 0.13 mmol) dissolved in tetrahydrofuran (2 ml) and dimethylformamide (1 ml) was added with (tert-butoxycarbonylmethylene)triphenyl-phosphorane (60 mg, 0.16 mmol) and refluxed by heating at 100° C. for 2 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=20:1) to obtain 36 mg (62%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][N:5]([CH3:7])[CH:6]=1.C1CN([P+](O[N:34]2N=[N:41][C:36]3C=CC=C[C:35]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([NH:41][CH2:36][C:35]#[N:34])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CC(C)C[C@H](Nc1nn(C)cc1Br)C(=O)O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nn(C)cc1Br)C(=O)NCC#N

Procedure:
To N-(4-bromo-1-methyl-1H-pyrazol-3-yl)leucine (366 mg, 1.26 mmol), PyBOP (725 mg, 1.39 mmol), aminoacetonitrile hydrochloride (257 mg, 2.78 mmol) in dry DMF (15 mL) under dry nitrogen was added triethylamine (0.62 mL, 4.45 mmol) dropwise and the reaction stirred for 2½ hours. Aqueous sat. NaHCO3 was added and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 6/4) to afford N2-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N1-(cyanomethyl)leucinamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CCC2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 0 °C
Yield: 55.3 %

Procedure:
This step was performed according to the method described in Journal of Medicinal Chemistry, 2006, 49, 7502-7512. 5-Methylindan-1-one (3.27 g, 22.4 mmol) was dissolved in concentrated sulfuric acid (27 ml), a solution of potassium nitrate (2.28 g, 22.6 mmol) in concentrated sulfuric acid (5 ml) was added dropwise over 10 min under ice-cooling with stirring, and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was added to ice water, and extracted with an ethyl acetate-hexane=1:1 mixed solvent. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.37 g, yield 55%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:4]3[CH:3]=[C:2]([F:1])[C:7]([OH:8])=[C:6]([F:9])[CH:5]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.10 mmol) and NCS (155 mg, 1.16 mmol) in THF (30 mL) according to method C to yield 264 mg (78%) of grey solid: mp 209–210° C.; 1H NMR (DMSO-d6): δ 7.32 (1H, d, J=8.89 Hz), 7.50–7.61 (2H, m), 7.83 (1H, d, J=8.96 Hz), 7.92 (1H, dd. J=8.94 Hz, J=1.59 Hz), 8.05 (1H, d, J=8.88 Hz), 8.22 (1H, d, J=1.19 Hz), 10.36 (1H, s), 10.54 (1H, s); MS (ESI) m/z 305/307 (M−H)−.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:2]([O:4][C:5]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:3]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(I)ccc1C(=O)OC
Yield: 98 %

Procedure:
2-Iodoethane (3.53 g) was added at room temperature to a mixture of methyl 2-hydroxy-4-iodobenzoate (4.19 g), potassium carbonate (4.17 g), and DMF (50 mL), and the resultant mixture was stirred at 70° C. for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.52 g).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:26])[O:6][CH2:7][C:8]1([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]=[C:9]1[O:19]C)([CH3:3])[CH3:2].I[Si](C)(C)C>C(#N)C>[CH:1]([NH:4][C:5](=[O:26])[O:6][CH2:7][C:8]1([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1=[O:19])([CH3:3])[CH3:2]
Reactant: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(C)CCC1(COC(=O)NC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of Example 180B (32 mg, 0.09 mmol) in acetonitrile (1 mL) was added iodotrimethylsilane (TMSI) (19 μL, 0.13 mmol). The reaction solution was stirred at room temperature for 3 h. After which, additional 1.5 equivalents of TMSI (19 μL) were added and stirring was continued for 2 h. The solution was quenched with water (2 mL) and extracted with ethyl acetate (2× 1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (70% ethyl acetate/hexane) afforded product as a white foam (24 mg, 77%). MS m/z 346.0 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].CO>O>[C:12]1([C:11]2[N:10]=[C:9]([S:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)COc1cccc(CSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cccc(CSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A mixture of methyl [3-[[(4,5-diphenyl-1H-imidazol-2-yl)thio]methyl]phenoxy]acetate (2.00 g, 4.6 mmol), lithium hydroxide monohydrate (586 mg, 14 mmol), methanol (35 mL) and water (10 mL) was stirred at room temperature for 2 hours. The solvent was evaporated, the residue diluted with water and 2N HCl solution added to pH=7. A white solid was filtered off and recrystallized from aqueous DMF to give [3-[[(4,5-diphenyl-1H-imidazol-2-yl)thio]methyl]phenoxy]acetic acid (1.33 g, 69%), m.p. 233°-235° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)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(c4ccccc4)CC3)nn2C(C)(C)C)cc1

Procedure:
125 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-phenylpiperazine (0.045 mL, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).