Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:3][CH:2]=1.[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[N+:22]([C:19]1[CH:20]=[CH:21][C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:9]([CH:18]=1)[C:10]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11])([O-:24])=[O:23]
Reactant: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(c1cc([N+](=O)[O-])ccc1Nc1ccncc1)N1CCCCC1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a solution of 20 g of 1-[2-(4-pyridinylamino)benzoyl]piperidine (Example 1b) in 75 ml of sulfuric acid cooled in an ice-salt bath was slowly added a solution of 6.5 ml of concentrated nitric acid in 65 ml of sulfuric acid. The mixture was stirred at 5° C. for four hours and then poured onto ice and allowed to stand overnight. A crystalline acid-addition salt formed which was collected, dissolved in water and converted to the free base by adding sodium bicarbonate. The free base product was extracted with methylene dichloride, the extracts dried over anhydrous sodium sulfate and concentrated, and the residue triturated with ethyl acetate to give 9.3 g of 1-[5-nitro-2-(4-pyridinylamino)benzoyl]piperidine as a yellow powder, m.p. 194°-196° C.(decompn.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][Cl:8].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl-:8].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COCOc1ccc(F)cc1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCOc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 69.6 %

Procedure:
3.25 g of 5-fluoro-2-methoxymethoxybenzyl chloride [prepared as described in step (c) above] were dissolved in 50 ml of toluene, and then 6.25 g of triphenylphosphine were added to the resulting solution. The resulting mixture was then heated under reflux for 6 hours. At the end of this time, the reaction solution was cooled. The resulting crystals were collected by filtration, and dried in vacuo, to give 5.16 g (yield 70%) of the title compound. Separately, the filtrate was concentrated by evaporation under reduced pressure, and the crystals which precipitated were collected by filtration, to give an additional 0.75 g (total yield: 80%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([OH:45])=[O:44]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([OH:45])=[O:44])=[CH:22][CH:23]=1)=[O:34])[CH3:9]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Product: Cc1noc(-c2ccc(-c3ccccc3CC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 19, Step 1 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester and 2-bromophenylacetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18].N1CCCCC1.O>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11][C:10]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccnc2)N1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccnc4)c32)c1C
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (53 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 80° C. for 2 hours, heating was stopped and the tube was shaken at room temperature for 2 days. A small amount of water was added to the reaction and the solid which formed was collected by vacuum filtration, washed with water and dried to give the title compound.
Reaction SMILES: C(OCCCC)CCC.[Na].[Na+].[Na+].[Na+].[P-3].[C:15]1([P:21](Cl)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:29](Cl)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O>[CH2:29]([P:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCl
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [P-3]
Solvent: CCCCOCCCC
Solvent: O
Product: CCCCCCP(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 88 %

Procedure:
Distilled di-n-butyl ether (2500 ml) and solid sodium metal (230 g, 10.0 moles) were placed in a 22 L round bottom flask. The flask was equipped as in the above Comparative Example C-1. The solution of the sodium phosphide salt was made by carefully adding diphenylphosphinous chloride (1100 g, 5.0 moles) to the refluxing solvent-sodium slurry as described in the previous example. Stirring and reflux was continued for 2 hours after addition of the diphenylphosphinous chloride was complete. The reaction mixture was cooled with further stirring to about 45° C. n-Hexyl chloride (603 g, 5 moles) was added over a 30 minute period. Stirring was continued for 30 minutes after this addition was complete. Water (2500 ml) was added with stirring and the inorganic salts dissolved. Stirring was stopped and the lower water layer drained off and discarded. The upper organic layer was concentrated under vacuum giving crude n-hexyldiphenylphosphine (1190 g) of about 87 percent yield based on diphenylphosphinous chloride. This material was found to be about 20 percent n-hexyldiphenylphosphine oxide by GLC analysis.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][C:26]1=[O:34].[C:35]([O-])([O-:37])=[O:36].[K+].[K+]>CN(C=O)C>[C:26]([OH:34])(=[O:8])[C:35]([OH:37])=[O:36].[O:34]=[C:26]1[N:25]([CH2:24][CH2:23][CH2:22][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27]1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)C(=O)O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1

Procedure:
To 50 ml dry DMF were added 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g, 0.0186 mole), 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (4.0 g 0.019 mole), milled K2CO3 (10 g, 0.07 mole) and KI (0.01 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[C:25](O)=[O:26])=[O:21].CCN=C=NCCCN(C)C.CCN(CC)CC>ClCCl>[CH:32]([O:31][C:30]1[CH:29]=[CH:28][C:24]([C:25]([N:17]2[CH2:18][CH2:19][C:14]3([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[O:13]3)[CH2:15][CH2:16]2)=[O:26])=[CH:23][C:22]=1[CH:20]=[O:21])([CH3:34])[CH3:33]
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1C=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (250 mg, 0.76 mmol), 3-formyl-4-isopropoxy-benzoic acid (160 mg, 0.76 mmol), EDCI (160 mg, 0.84 mmol), and Et3N (430 μL, 3.1 mmol) were combined in dichloromethane (7.1 mL) and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with a 1 M HCl (×2), a saturated aqueous solution of NaHCO3 (×2) and a saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in dichloromethane) to yield 2-isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde (117 mg, 34%) as a light yellow solid. ESI-MS m/z calc. 445.2, found 446.3 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O>O1CCCC1>[ClH:24].[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([Cl:24])=[O:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)O)ccc3o2)n1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)Cl)ccc3o2)n1
Product: Cl
Temperature: 25 °C

Procedure:
A solution of 2-(4-tert-butylthiazol-2-yl)benzofuran-5-carboxylic acid (5.0 g) and thionyl chloride (12.1 ml) in tetrahydrofuran (50 ml) was stirred at 50° C. for 2 hours. After the solution was cooled to room temperature, the resulting precipitates were collected by filtration and washed with diisopropyl ether to give 2-(4-tert-butylthiazol-2-yl)benzofuran-5-carbonyl chloride hydrochloride (5.57 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]#[C:13][CH2:14]O)[C:8]=2[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]P(Br)Br>ClCCl>[Br:20][CH2:14][C:13]#[C:12][C:9]1[C:8]([C:16]([F:19])([F:18])[F:17])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11][N:10]=1
Reactant: OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: FC(F)(F)c1c(C#CCBr)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-yn-1-ol (Preparation 62B, 0.465 g, 1.740 mmol) in dichloromethane (9.0 mL) at 0° C. was added a 1.0 M solution of tribromophosphine in dichloromethane (2.09 mL, 2.09 mmol). After 5 min., the ice-bath was removed, and the reaction mixture was stirred at room temperature overnight. HPLC and LCMS analysis indicated that there was still significant starting material remaining. Additional tribromophosphine (1.0 M in dichloromethane) (2.09 mL, 2.09 mmol) was added, and the reaction mixture was stirred at room temperature for 4.5 h. Additional tribromophosphine (1.0 M in dichloromethane) (2.09 mL, 2.09 mmol) was added, and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure provided the crude product, which was loaded with a minimum amount of dichloromethane on a fitted funnel containing a layer of Celite topped with a layer of silica gel. The plug column was eluted with a mixture of ethyl acetate and hexane (1%-3%) to give 3-(3-bromoprop-1-ynyl)-5-phenyl-4-(trifluoromethyl)isoxazole (0.219 g, 0.663 mmol, 38% yield) as a clear, colorless oil. The product had an HPLC ret. time=2.95 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=331.93.
Reaction SMILES: N(C(OC(C)C)=O)=N[C:3](OC(C)C)=O.[OH:15][C:16]1[CH:39]=[CH:38][C:19]2[CH2:20][C@@H:21]([CH2:34][C:35]([O-:37])=[O:36])[C:22](=[O:33])[N:23]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24][C:18]=2[CH:17]=1.[CH3:40][NH:41][C:42]1[N:47]=[C:46]([CH:48](O)[CH3:49])[CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:40][NH:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][O:15][C:16]2[CH:39]=[CH:38][C:19]3[CH2:20][C@@H:21]([CH2:34][C:35]([O:37][CH3:3])=[O:36])[C:22](=[O:33])[N:23]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][C:18]=3[CH:17]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: CNc1cccc(C(C)O)n1
Reactant: O=C([O-])C[C@@H]1Cc2ccc(O)cc2CN(CCc2ccccc2)C1=O
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNc1cccc(CCOc2ccc3c(c2)CN(CCc2ccccc2)C(=O)[C@H](CC(=O)OC)C3)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
Diisopropyl azodicarboxylate (0.3 mL, 1.5 mmole) was added to a solution of (S)-8-hydroxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (350 mg, 1.0 mmole), 6-(methylamino)-2-pyridylethanol (228 mg, 1.5 mmole), and triphenylphosphine (393 mg, 1.5 mmole) in anhydrous THF (10 mL) at 0° C. The mixture was allowed to warm to RT over 72 hr then was concentrated. Flash silica gel chromatography (50% EtOAc/hexanes) followed by a second flash silica gel chromatography (25% EtOAc/hexanes) gave the title compound as a white foam (250 mg, 51%): MS (ES) m/e 488 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:9](=[O:11])[CH2:8][S:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(O)CSc1ccncc1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)CSc1ccncc1
Yield: 33.7 %

Procedure:
Using the general method of Example 105 (4-pyridylthio)acetic acid (0. 11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide 0.1 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-pyridylsulfanyl)acetamide as a solid, m.p. 127.5-129° C.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>CC#N.O>[C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1cccc(N(c2ccccc2)C2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1CCC(N(c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To solution of N-phenyl-N-(3-(trifluoromethyl)phenyl)piperidin-4-amine (1.3 g, 4.1 mmol) in MeCN (15 mL) was added ethyl bromoacetate (0.50 ml, 4.5 mmol) followed by triethylamine (1.1 ml, 8.1 mmol). The reaction mixture was stirred at RT for 4 h, diluted with water and extracted with DCM. The combined DCM layer was dried (Na2SO4), and concentrated. The product was purified with ISCO using 0-15% EtOAc in DCM to give ethyl 2-(4-(phenyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)acetate (1.2 g, 73% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][CH:26]([CH2:37][CH3:38])[CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([CH2:27][CH:26]([CH3:25])[CH2:37][CH3:38])=[CH:29][CH:30]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCC(C)Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)cc3)cc2)cc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
This 4-hydroxy-4'-n-decyloxybiphenyl (0.5 g) was dissolved in dry pyridine (20 ml), followed by dropwise adding to the solution, commercially available (+)-p-(2-methylbutyl)benzoyl chloride (0.4 g), further pouring dry toluene (15 ml) in the mixture, sufficiently shaking at room temperature, further heating on a water bath at 60° C. for 3 hours, cooling down to room temperature, adding toluene (50 ml), twice washing with 6N hydrochloric acid (100 ml), further twice washing with a 2N alkali aqueous solution, several times washing with saturated NaCl aqueous solution to make the liquid neutral, drying over sodium sulfate, distilling off toluene, filtering through active carbon on heating using a mixed solvent of ethanol (20 ml) and ethyl acetate (20 ml), recrystallizing, filtering crystals deposited in a refrigerator, and drying to obtain the objective 4-n-decyloxy-4'-(p-(2-methylbutyl)benzoyloxy)biphenyl (0.3 g). Its phase transition points are shown in Table 3, sample No. 10. Further, its values of elemental analysis accorded well with its theoretical values as follows:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][CH2:23]OS(C)(=O)=O)[N:18]=2)[S:5][C:6]=1[C:7](=[O:16])[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH2:36](Cl)Cl>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:7]([CH:6]2[S:5][C:4]([C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:18]=3)=[N:3][C:2]2([CH3:36])[CH3:1])=[O:16])[CH:11]=1
Reactant: ClCCl
Reactant: Cc1nc(-c2ccn(CCOS(C)(=O)=O)n2)sc1C(=O)NCc1cccnc1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)N=C(c2ccn(CCNc3ccccc3)n2)SC1C(=O)NCc1cccnc1
Temperature: 85 °C
Yield: 52 %

Procedure:
To a solution of methanesulfonic acid 2-(3-{4-methyl-5-[(pyridin-3-ylmethyl)-carbamoyl]-thiazol-2-yl}-pyrazol-1-yl)-ethyl ester (0.19 g, 0.45 mmol) in methylene chloride (2 mL) was added aniline (0.91 mL, 9.93 mmol). The reaction mixture was heated under nitrogen at 85° C. for 16 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed with NaHCO3 (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 4-methyl-2-[1-(2-phenylamino-ethyl)-1H-pyrazol-3-yl]-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide as a white solid (0.052 g, 52%). 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.58 (d, J=4 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.32-7.37 (m, 1H), 7.17-7.23 (m, 2H), 6.83 (d, J=2 Hz, 1H), 6.76 (t, J=8 Hz, 1H), 6.63 (d, J=5 Hz, 2H), 6.18-6.23 (m, 1H), 4.67 (d, J=8 Hz, 2H), 4.38 (t, J=4 Hz, 2H), 3.68 (t, J=4 Hz, 2H), 2.77 (s, 3H); MS (M+H)+=419.2; Rt=1.23 min; HRMS (M+H)+=419.17.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].C([Mg]Cl)(C)C.[B:17](OC)([O:20]C)[O:18]C>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([B:17]([OH:20])[OH:18])[CH:3]=1)#[N:6]
Reactant: COc1ccc(C#N)cc1Br
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1B(O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
3-Bromo-4-methoxybenzonitrile (3.0 g, 14.2 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mLs). The solution cooled at −10° C. and stirred while isopropylmagnesium chloride (17.7 mmol, 8.8 mLs, 2.0 M in THF, 1.25 eq.) was added. The mixture was stirred for 1 hour and then trimethyl borate (1.87 g, 17.7 mmol, 2.0 mL) was added dropwise. The mixture was allowed to warm slowly to room temperature for 1 hour. The solvent was evaporated and the residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to a minimum volume under reduced pressure. The residue was recrystallized from hexanes to give 5-cyano-2-methoxybenzeneboronic acid (2.48 g, 99%) as a fluffy white powder.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.CC1C=CC(S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O)=CC=1.O>CN(C=O)C.C(OCC)(=O)C>[F:25][C:24]([F:27])([F:26])[CH2:23][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.8 %

Procedure:
Sodium hydride (787 mg, 55%, 18.0 mmol) was suspended in DMF (10 mL) under a nitrogen atmosphere, and a solution of DMF (5 mL) containing 4-hydroxybenzaldehyde (2.00 g, 16.4 mmol) was dropwise added thereto over 5 minutes at room temperature. A light yellow insoluble substance was precipitated immediately after the addition. After 5 minutes, a solution of DMF (5 mL) containing 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (4.00 g, 17.2 mmol) was added dropwise thereto to give a brown solution. This brown solution was stirred at room temperature for 1 hour, and then water (100 mL) and ethyl acetate (150 mL) were added thereto. The organic layer was separated, further washed with water (50 mL) five times, with a 10% sodium hydroxide aqueous solution (50 mL) three times, and with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a crude product. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate, 5:1, v/v) to give 1.40 g of the title compound (light yellow oil, yield: 42%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[CH:10][N:9]=[C:8]([NH2:13])[N:7]=1.[C:14](#[N:17])[CH:15]=[CH2:16].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:13][C:8]1[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:11](/[CH:16]=[CH:15]/[C:14]#[N:17])=[CH:10][N:9]=1
Reactant: Nc1ncc(I)c(-c2ccco2)n1
Reactant: C=CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#C/C=C/c1cnc(N)nc1-c1ccco1

Procedure:
From 4-furan-2-yl-5-iodo-pyrimidin-2-ylamine, acrylonitrile, bis(triphenyl-phosphine)palladium(II) chloride and cesium carbonate in dioxane. EI-MS m/e (%): 212 (M+, 52), 195 ([M—NH3]+, 100), 184 (32), 158 (52).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=O.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N:18]1([C:11]2[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: Nc1ccccc1Sc1ccccc1C(=O)O
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2

Procedure:
simultaneously conducting cyclization and chlorination reactions of 2-(2-aminophenylthio)benzoic acid which is expressed by Formula 7 in an organic solvent in the presence of a halogenating agent and a base, and continuously reacting a resulting compound with piperazine without separation, to produce 11-piperazinyl-dibenzo[b,f][1,4]thiazepine expressed by Formula 4; and