Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:14]([NH2:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21].[OH-:23].[K+]>C(Cl)CCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:22][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][C:5]([O:23][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1
Reactant: NCCCCCCCN
Agent: [K+]
Solvent: ClCCCl
Product: CC(C)Oc1ccc(C(=O)NCCCCCCCNC(=O)c2ccc(OC(C)C)cc2)cc1

Procedure:
m.p. 135°-136° C., 10.9 g., was prepared as in Example 1 using a solution of 4-isopropoxybenzoyl chloride (from 18.0 g. of 4-isopropoxybenzoic acid as in Example 6) in 100 ml. of ethylene dichloride, 8.9 g. of 1,7-heptanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. ethylene dichloride and recrystallization from acetonitrile using decolorizing charcoal.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30]CCC(Cl)=O.[CH2:36]1C[O:39][CH2:38][CH2:37]1>>[Cl:30][C:10]1[C:2]([NH:1][C:38](=[O:39])[CH2:37][CH3:36])=[CH:3][CH:4]=[C:5]2[C:9]=1[C:8](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:7][CH2:6]2
Reactant: O=C(Cl)CCCl
Reactant: C1CCOC1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc2c(c1Cl)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 3-chloropropionyl chloride (21.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (58.8 mg, 84%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:17].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO>[CH2:16]([O:18][C:19]1[CH:29]=[C:28]([CH:30]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:27]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:17]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: CCOC(=O)c1ccc(C=O)cc1OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc1OCC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 1,2-diphenylethanone (53 mg, 0.270 mmol), ethyl 2-ethoxy-4-formylbenzoate (Intermediate 48) (50 mg, 0.225 mmol) and urea (41 mg, 0.675 mmol) in EtOH (2.5 mL) was added concentrated HCl (0.1 mL). The mixture was stirred at 90° C. for 16 h. The volatiles were removed under reduced pressure to afford crude ethyl 2-ethoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate, which was dissolved in THF/H2O/MeOH (v/v/v=1/1/1, 0.6 mL) followed by addition of lithium hydroxide monohydrate (14 mg, 0.338 mmol). The solution was stirred at room temperature overnight. Most of THF and MeOH were evaporated under reduced pressure and the resulting aqueous solution was acidified with 10% hydrochloric acid to pH=6.0. The resulting precipitate was purified by prep-HPLC to afford Compound 97 as a white powder (11 mg, 12%). 1H NMR (MeOH-d4 500 MHz): δ 7.68 (d, J=8.0 Hz, 1H), 7.14 (s, 5H), 6.94-6.98 (m, 4H), 6.89 (s, 1H), 6.76 (t, J=3.5 Hz, 2H), 5.26 (s, 1H), 3.90-4.00 (m, 2H), 1.27 (t, J=7.0 Hz, 3H); MS (ESI): m/z 415.1 [M+1]+.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Na+].[OH-].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.Cl>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:13][CH:12]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Sodium pyruvate (24.2 g, 0.22 moL) was added to a cold (0° C.) solution of 1N sodium hydroxide (200 mL) and ethanol (10 mL). p-Chlorobenzaldehyde (28.11 g, 0.20 moL) was then added, maintaining the temperature below 5° C. The reaction mixture was aged six hours at 0°-5° C. and then allowed to warm to 20° C. where it was aged an additional six hours to effect complete reaction. The mixture was cooled to -10° C. and the pH adjusted to 1.0 with cold 6N HCl. The p-chlorobenzalpyruvic acid product was then extracted with 800 mL ethyl acetate in 94% yield.
Reaction SMILES: [NH3:1].CS(O[CH:7]1[CH2:10][N:9]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)(=O)=O>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:9]2[CH2:10][CH:7]([NH2:1])[CH2:8]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: N
Solvent: CO
Product: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -60 °C
Reaction time: 24 h

Procedure:
1[Bis(4-chlorophenyl)methyl]azetidin-3-ylamine may be obtained in the following manner:400 cm3 of a mixture of methanol and liquid ammonia (50/50 by volume) are added to 27 g of 1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl methylsulfonate contained in an autoclave previously cooled to around −60° C. The reaction medium is then stirred at 60° C. for 24 hours and then abandoned in the open air in order to allow the evaporation of the ammonia and finally concentrated under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of a 0.37 N aqueous sodium hydroxide solution and extracted with four times 500 cm3 of ethyl ether. The combined organic phases are washed successively with twice 100 cm3 of distilled water and 100 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethan/methanol (95/5 by volume)]. 14.2 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3ylamine are obtained in the form of an oil which solidifies into a cream-colored solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][N:15]([CH2:18][C:19]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[O:20])[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Reactant: O=C(CBr)c1ccsc1
Agent: Cl
Product: O=C(CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1)c1ccsc1

Procedure:
Prepared according to the method of Example 2 using 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4) and 2-bromo-1-(3-thienyl)ethanone. 1H NMR (500 MHz, d6-DMSO) δ 10.51 (1H, s), 8.52 (1H, s), 7.96 (2H, dd, J=5.1, 8.7 Hz), 7.72 (1H, dd, J=2.8, 5.0 Hz), 7.55 (2H, t, J=8.8 Hz), 7.49 (1H, d, J=4.3 Hz), 4.91 (2H, s), 4.19 (2H, s), 4.00 (2H, s), 3.82 (2H, d, J=6.7 Hz), 3.10–3.03 (1H, m); m/z (ES+) 354 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C@@H:18]([CH2:21][CH3:22])[CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][C@@H:18]([CH3:19])[CH2:21][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC[C@H](C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 41 %

Procedure:
3.75 g of 4-hydroxybiphenyl-4'-carboxylic acid was heated under reflux together with (S)-2-methylbutyl alcohol in the presence of 0.10 g of p-toluenesulfonic acid for about 6 hours. Then the mixture was filtered to remove the unreacted 4-hydroxybiphenyl-4'-carboxylic acid. Next, the filtrate was evaporated and the unreacted (S)-2-methylbutyl alcohol was distilled off. The crystals thus obtained were recrystallized from 200 ml of n-hexane. Thus, 2.05 g of the corresponding colorless compound was obtained (Yield: 41%).
Reaction SMILES: B(F)(F)F.[CH3:5][C:6]([S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=1)([CH3:11])[CH2:7]C(=O)C.[C:28]([C:32]1[CH:37]=[C:36]([SH:38])[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]=1[OH:43])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:5][C:6]([S:12][C:13]1[CH:14]=[C:15]([C:24]([CH3:27])([CH3:25])[CH3:26])[C:16]([OH:23])=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:18]=1)([CH3:11])[CH2:7][C:6]([S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:16]([OH:23])=[C:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:14]=1)([S:38][C:36]1[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([OH:43])=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:37]=1)[CH3:5]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CC(C)(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC(C)(CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
0.11 Grams of BF3 -etherate is added to a solution of 2.70 grams of the product from (a) and 4.14 grams of 2,6-di-tert- butyl-4-mercaptophenol dissolved in 30 ml of toluene. The mixture is heated at 55°-65° C. for nine hours and 105°-110° C. for three additional hours. The toluene solution is washed with water and dried over sodium sulfate. The residue, isolated by evaporation of the solvent by distillation in vacuum, is purified by passing a solution in 70:30 heptane:toluene through a flash chromatographic column using silica gel. The isolated residue solidifies on cooling, and melts at 93°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:28](Cl)(=[O:30])[CH3:29]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28](=[O:30])[CH3:29])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cc(C)cc(Cl)c2)cc1
Yield: 70 %

Procedure:
To a suspension of 4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.30 g, 0.72 mmol) in 1.5 mL of acetic acid was added 1.5 mL of acetyl chloride at room temperature. The mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was concentrated under vacuum and the residue was treated with ether to give 0.23 g (70%) of N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a white solid: mp (DSC) 232-235 _C. Anal. Calc'd. for C19H15ClF3N3O3S: C, 49.84; H, 3.30; N, 9.18; S, 7.00. Found: C, 49.72; H, 3.48; N, 8.81; S, 7.18.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1C=CN=C1.S(Cl)(C)(=O)=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N+:53]=1[O-:58]>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N+:53]=3[O-:58])=[O:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1cccc[n+]1[O-]
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2cccc[n+]2[O-])CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (176 mg, 0.327 mmol) in DMF (2 ml) was added 1-methylimidazole (52 μl, 0.655 mmol) and cooled to 0° C. Mesyl chloride (27 μL, 0.344 mmol) was added dropwise at 0° C., and the resulting mixture was stirred for 30 min followed by the addition of 2-amino pyridine N-oxide (36 mg, 0.327 mmol). The reaction was warmed to rt. After 2 h, the reaction mixture was concentrated, diluted with methanol, and purified by reverse phase HPLC to afford 105 mg (0.167 mmol, 51%) of the title compound. LC/MS: (M+H)+: 629.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:17].C(O)(=O)C>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([O:13][CH3:17])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C)(C)CC(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CC(C)(C)c1ccc(OC)cc1
Reaction time: 0.75 h

Procedure:
3-(4-methoxyphenyl)-3-methylbutanoic acid (513 mg, 2.463 mmol) was dissolved in toluene (13.3 ml) and methanol (2 ml). TMS-diazomethane (1.848 ml, 3.70 mmol) was added dropwise. Evolution of gas was observed, and a yellow color persisted. After 45 minutes, the reaction was quenched with acetic acid (200 uL, 3.5 mmol). The reaction was concentrated, and the residue was purified by flash chromatography on silica gel with 0 to 75% EtOAc/hexanes to afford methyl 3-(4-methoxyphenyl)-3-methylbutanoate. 1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 3.54 (s, 3H), 2.59 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:40])[NH2:39])[CH:34]=2)[CH:29]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:7][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:39])[NH2:40])[CH:34]=2)[CH:29]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)CC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 1.8 g of isovaleric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with a small volume of pyridine, then with acetone, and dissolved in methanol at room temperature. The insolubles were collected by filtration and washed with a small volume of methanol. The filtrate and the washings were concentrated under reduced pressure and admixed with ethyl ether. The precipitated crystals were recrystallized from an ethanol-methanol (9:1) mixture to yield 2.0 g of colorless flaky crystals of 6-amidino-2-naphthyl isovalerate methanesulfonate.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:20])[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25](O)[CH:24]=1>>[CH3:4][C:2]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([O:20][C:29]1[CH:30]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=1[C:27]#[N:28])[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:1])[CH3:3]
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: COc1ncccc1C(O)CCCNC(=O)OC(C)(C)C
Product: COc1ncccc1C(CCCNC(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The sub-title compound was prepared by the method of Example 1 step (b) using the product of step (b) above and 4-chloro-2-hydroxybenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18]O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:50]3[C:46](=[O:56])[C:47]4[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:49]3=[O:51])[CH2:11][CH2:10]2)=[CH:21][CH:22]=1
Reactant: OCCCCC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
23.1 g (62.5 mmol) 4-{1-[bis(4-fluorophenyl)-methyl]-piperidin-4-yl}-butan-1-ol, 16.4 g (62.5 mmol) triphenylphosphine and 9.2 g (62.5 mmol) phthalimide are suspended in THF and 10.9 g (62.5 mmol) azodicarboxylic acid diethyl ester is added dropwise under a protective atmosphere and light cooling (ca. 15-25° C.). The mixture is stirred for three hours at RT and subsequently the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CH2Cl2/CH3OH (99.5/0.5) Yield: 27.6 g (90%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O.[CH3:22][NH:23][CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)CCl>[CH3:22][N:23]([CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:24]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-formylphenyl)piperazinecarboxylate (Step 1) (0.6 g, 2.1 mmol), was added dimethylamine (Aldrich) (1.6 mL of a 2.0 M soln in THF, 3.2 mmol) in ClCH2CH2Cl (15 mL) and NaBH(OAc)3 (Aldrich) (0.66 g, 3.2 mmol). The reaction was stirred at RT for 2 h. The mixture was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-{2-[(dimethylamino) methyl]phenyl}piperazinecarboxylate (0.68 g) as a yellow oil. MS m/z: 320 (M+H). Calc'd for C18H29N3O2: 319.44.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[C:21]([OH:24])(=[O:23])[CH3:22]>CS(C)=O.O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:9]2[C:2]([CH3:1])=[C:3]([CH:4]=[CH:4][CH2:3][CH2:2][CH2:9][CH2:8][CH2:22][C:21]([OH:24])=[O:23])[CH:6]=[CH:7][CH:8]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: Cc1c(C=O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1c(C=CCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 2 °C
Reaction time: 16 h

Procedure:
A solution of 2.585 g of 2-methyl-3-(4-chlorobenzoyl)benzaldehyde and 5.49 g of ω-carbethoxyhexyl triphenyl phosphonium bromide in 25 ml of a 1:1 dimethylsulfoxidetetrahydrofuran mixture was added with stirring in 3 minutes to 520 mg of a 60% oil suspension of sodium hydride in 15 ml of a 1:1 dimethylsulfoxide-tetrahydrofuran mixture cooled to 2° C. and stirring was continued for 16 hours at 24° C. after the temperature had risen. The mixture was then cooled to 5° C. and 2 ml of acetic acid were added thereto. The solvents were removed and the residue was empasted with isopropyl ether and then filtered to remove insolubles. The filtrate was evaporated and the residue was saponified in a mixture of 50 ml of methanol and 15 ml of a 2 N sodium hydroxide solution at 80° C. for 1 hour. The methanol was removed and water was added. The mixture was extracted with ether and the aqueous phase was treated with activated carbon, filtered and acidified with concentrated hydrochloric acid. The oily residue was extracted with ether and the ether phase was washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to obtain 2.98 g of 8-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-oct-7-enoic acid with an Rf=0.35 (8:2 CH2Cl2 -acetone mixture).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[S:19](Cl)([Cl:22])(=[O:21])=[O:20]>CCOCC.C(OCC)(=O)C>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Temperature: -78 °C
Yield: 49.5 %

Procedure:
3-Bromobiphenyl (1.5 g, 6.4 mmol) was dissolved in ether (15 ml) and cooled to −78° C. t-Butyllithium (1.7 M solution in hexane, 3.8 ml, 6.4 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at −10° C. to −5° C. for 6 h. The reaction mixture was cooled to −78° C. and sulfuryl chloride (0.64 ml, 6.4 mmol) was added dropwise. After completion of the addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgSO4. Removal of the solvent under reduced pressure gave crude product, which was purified by column chromatography, using hexane followed by 5% ethyl acetate in hexane as eluent, to give 3-biphenylsulfonyl chloride as an oil (0.8 g, 49% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:23][CH:24]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)nn2)cs1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cs1
Yield: 79.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(6-chloropyridazin-3-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 213-1 and 4-trifluoromethoxyphenylboric acid (300 mg) were dissolved in dioxane (6 mL) and 2 mol/L sodium carbonate (3 mL), tetrakis(triphenylphosphine)palladium (70 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:2) to give the title compound (520 mg).