Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:50])[CH2:29][NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:4]=[N:3]1.[H-].[Na+].[CH3:53]I.O>CN(C)C=O>[CH3:53][N:27]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:28](=[O:50])[CH2:29][NH:30][C:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CI
Reactant: Cn1ncc(NC(=O)CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a stirred solution of N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-(tritylamino)acetamide (2 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (245 mg, 60% oil suspension) at 0° C., and the mixture was stirred for 30 minutes with warming to room temperature. The mixture was cooled to 0° C., and methyl iodide (1.3 g) was added. The whole mixture was stirred at room temperature overnight. Water (5 ml) was added, and the whole mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave N-methyl-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-(tritylamino)acetamide (2.05 g).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[CH3:19][CH:20]([CH3:46])[CH:21]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:34]1[CH:33]=[CH:32][C:31]([CH:21]([CH:20]([CH3:46])[CH3:19])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:36][CH:35]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C(C)C)cc1
Yield: 15 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (500 mg, 1.54 mmol) was reacted with tert-butyl 3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (590 mg, 1.9 mmol) to afford the desired product (120 mg, 15%) as a yellow solid: ESI MS m/z 507 [C29H34N2O4S+H]+.
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27](F)=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([O:20][C:27]2[C:28]([CH3:30])=[N:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@H](O)[C@H]1CCN(Cc2ccccc2)C1
Reactant: Cc1nc(Cl)ccc1F
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cl)ccc1O[C@@H](CC(C)C)[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Charge a 200 mL round bottom flask equipped with a Claisen adaptor, thermal couple and N2 inlet with (S)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)-pyrrolidine (5.69 g, 23 mmoles) and DMA (58 mL). Add NaH (1.29 g, 32.2 mmoles) in one portion with stirring and stir at room temperature for 1 hour. Add 6-chloro-3-fluoro-2-methylpyridine (3.52 g, 24.15 mmoles) in one portion with stirring and then stir at room temperature for 24 hours. Quench the reaction mixture with H2O (120 mL) and extract with MTBE (120 mL). Wash the organic layer with H2O (2×60 mL), followed by brine (60 mL), and then dry over Na2SO4. Filter, concentrate, and then purify the crude material (in toluene) by loading onto silica (225 g, wet with toluene) and eluting with the following: hexanes (2×500 mL), 15% MTBE/hexanes (16×500 mL), 50% MTBE/hexanes (8×500 mL). Concentrate the appropriate fractions to give (S)-1-benzyl-3-((S)-1-(6-chloro-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine as a light yellow oil (5.77 g, 15.47 mmoles, 67% yield, purity >98%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 7.06 (s, 2H), 4.32-4.20 (m, 1H), 3.68-3.48 (m, 2H) 2.78-2.64 (m, 2H), 2.64-2.30 (m, 2H), 2.42 (s, 3H), 2.28-2.20 (m, 1H), 2.05-1.85 (m, 1H), 1.82-1.52 (m, 4H), 1.48-1.34 (m, 1H), 0.92 (d, 3H, J=6.45 Hz), 0.88 (d, 3H, J=6.45 Hz). LC/MS=373.2 (M), 375.3 (M+2).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[OH-].[Na+].CS(C)=O.Cl[CH2:18][CH2:19][CH2:20][Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:18][CH2:19][CH2:20][Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])[CH:2]=[CH2:3]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: C=CCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C=CCc1ccccc1OCCC[Si](OC)(OC)OC
Temperature: 115 °C
Yield: 90 %

Procedure:
Using the general procedure described in Example 1 a reactor was charged with 73.7 g (0.55 mole) of o-allylphenol, 43.28 g of a 50% by weight aqueous solution of sodium hydroxide (0.54 mole NaOH), 112 cc dimethylsulfoxide and 120 cc toluene. The resultant mixture was heated to the boiling point for six hours under a nitrogen atmosphere to remove all of the water present by azeotropic distillation. The reaction mixture was then allowdd to cool to about 75° C., at which time 109 g (0.56 mole) of 3-chloropropyl trimethoxysilane was added dropwise while the reaction mixture was stirred. Following completion of the addition the reaction mixture was heated at 115° C. for about 16 hours, following which the mixture was allowed to cool and was filtered to remove any solid material. The solvents were then removed under a pressure of about 15 mm of mercury at a temperature of about 60° C. The pressure was then reduced to 2 mm of mercury and the material boiling at 146° C. was collected. The weight of this fraction was equivalent to a yield of 90% based on starting materials. Analysis by vapor phase chromatography indicated that the purity of the product was greater than 98%. The infrared and nuclear magnetic resonance spectra of the product were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[Br:16]Br.[Cl-].[NH4+]>O1CCCC1>[Br:16][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: BrBr
Reactant: COc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1Br
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-difluoroanisole (2 mL) in tetrahydrofuran (50 mL) was added n-butyllithium (2.67 mol/L n-hexane solution, 6.95 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added bromine (1.04 mL), and the mixture was stirred at −78° C. for 15 minutes. The mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane −n-hexane/ethyl acetate=9/1) to give the title compound (0.91 g)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[C:24]([CH2:25]O)=[C:23]([CH:27]([CH3:29])[CH3:28])[N:22]=[N:21]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=1[N:20]1[C:24]([CH2:25][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=2)=[C:23]([CH:27]([CH3:29])[CH3:28])[N:22]=[N:21]1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a 0° C. suspension of 4′-hydroxy-2′-methylacetophenone (969 mg, 6.45 mmol), [3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (1.85 g, 6.45 mmol), tri-n-butylphosphine (2.42 ml, 9.73 mmol) in toluene (20 mL) is added ADDP (2.46 g, 9.73 mmol). The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is concentrated and the residue is chromatographed eluting with 0% to 30% EtOAc/Hex to yield the title compound (1.71 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, 1H, J=8.5, 2.1 Hz), 7.72 (d, 1H, J=1.3 Hz), 7.49 (d, 1H, J=2.2 Hz), 7.47 (s, 1H), 7.41 (dd, 1H, J=9.2, 6.6 Hz), 6.78 (d, 1H, J=8.4 Hz), 4.99 (s, 2H), 3.22 (sept, 1H, J=7.0 Hz), 2.52 (s, 3H), 2.06 (s, 3H), 1.46 (d, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][N:14](C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O.[NH2:20]N>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1ccc(C(=O)CCN(C)C)cc1OC
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNCC2)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 1-(3,4-dimethoxy-phenyl)-3-dimethylamino-propan-1-one.HCl, (1.4 g, 5 mmol) EtOH, (20 mL) and hydrazine monohydrate, (0.3 mL, 6 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained 1030 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 207 (M+H). Step 3
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19]>[B-](F)(F)(F)F.[Ag+].O>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: CC(C)=O
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 8) in 100 ml. of acetone and 65 ml. of water is added 8.0 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride and extracted with half saturated sodium bicarbonate solution. The basic extract is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil with the properties described in Example 27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-chlorophenylbenzene (7.02 g, 37.2 mmol) in 70 mL of dichloromethane is treated with chlorosulfonic acid (4.55 g, 39.1 mmol) at RT. The reaction is stirred for 2 h further, and the formed precipitate is collected by vacuum filtration, washed with dichloromethane and dried to afford 9.6 g (96%) of 4′-chlorobiphenyl-4-sulfonic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:14]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:23][OH:24]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:14]=[N:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To the title compound of Example 2.1 (3.0 g, 14.1 mmol) in MeOH/H2O (30 mL/30 mL) in an ice-bath was added Na2CO3 (895 mg, 8.4 mmol) and hydroxylamine hydrochloride (1.2 g, 16.9 mmol). After stirring for 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated to half volume and then extracted with ethyl acetate (2 times), washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.1 g, 97%).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (2.69 g, 8.73 mmol) and triethylamine (2.44 mL, 17.5 mmol) in THF (60 mL) at 0° C. was added 1-methylpiperazine (0.98 mL, 8.83 mmol). The reaction was warmed to room temperature and allowed to stir overnight. The solution was concentrated and then diluted with water and extacted with ethyl acetate (3 times). The combined organic layers were dried with MgSO4, filtered, and concentrated. Flash chromatography (80% ethyl acetate/20% Ethanol) on silica gel gave the title compound (2.45 g, 76%). EI-MS m/z 372(M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2) The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (501 mg, 76%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[N+:25]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[NH2:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH2:16][CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(CCNC2CCN(Cc3ccccc3)CC2)c1
Solvent: CO
Product: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1

Procedure:
26.0 g (70.3 mmol) (1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine were hydrogenated with 5.0 g (2.45 mmol) rhodium charcoal (5%, moistened with water) in 350 mL methanol in a 3 bar hydrogen atmosphere for 3 h at RT. The catalyst was removed by suction filtering and the solution concentrated by rotary evaporation. The residue was immediately reacted further without any further purification.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([O:13]C(OCC2C=CC=CC=2)=O)=[CH:9][CH:8]=1)[CH2:3][CH3:4].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][CH:2]([O:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCC(C)OC(=O)c1ccc(OC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)c1ccc(O)cc1
Yield: 92.7 %

Procedure:
A solution of 10 m moles(3.1 g) of the above 4-carbobenzoxyoxybenzoic acid 1-methylpropyl ester and 0.5 g of palladium carbon (5% catalyst) in 40 ml of ethyl acetate was reacted for four hours in an atmosphere of hydrogen gas. After the reaction, palladium carbon was filtered out using a membrane filter, and the filtrate was concentrated, then purified by column chromatography to obtain 1.7 g of 4-hydroxybenzoic acid 1-methylpropyl ester. (yield: 86%)
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O.[Cl-]>C(Cl)(Cl)Cl>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10 g of α-linolenic acid in 100 ml of anhydrous chloroform was kept cooled with ice and 4.6 g of oxalic chloride was added dropwise thereto. The solution containing the chloride was stirred at room temperature for three hours. The resultant reaction solution was dried under a vacuum. The α-linolenic acid chloride consequently formed was dissolved in 100 ml of anhydrous chloroform. The solution consequently obtained was cooled to -50° C. and 2.2 g of paraformaldenyde was added thereto and subsequently 12.2 g of zinc chloride was added thereto. Thereafter, the resultant reaction solution was stirred at room temperature for three hours. It was subjected to alumina chromatography. From the methylene chloride eluate consequently separated, 4.1 g of α-linolenyl oxymethyl chloride was obtained. The physicochemical data obtained of this product were as shown below. They prove the identity of α-linolenyl oxymethyl chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=O.[C:8]([C:11]1[C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][N:14]([C:16]2([CH2:20][C:21]#[N:22])[CH2:19][NH2+:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].FC(F)(F)S(OCC(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[C:21]([CH2:20][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13]2)[CH2:17][N:18]([CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:19]1)#[N:22]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)C[NH2+]C1
Reactant: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CN(CC(F)(F)F)C1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (23 mg, 0.078 mmol) in dioxane (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (36 mg, 0.15 mmol), followed by K2CO3 (23 mg, 0.078 mmol). The resulting mixture was heated to 110° C. and allowed to stir for 2 hours. The reaction was then cooled to ambient temperature, water was added and the reaction mixture was extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound, Example #19. 1H NMR (600 MHz, CDCl3): δ 8.78 (s, 1H), 7.75 (s, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.26 (t, J=7.9 Hz, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.62 (s, 2H), 3.81 (d, J=8.6 Hz, 2H), 3.74 (d, J=8.6 Hz, 2H), 3.34 (s, 2H), 3.09 (q, J=9.1 Hz, 2H). LRMS (ESI) calc'd for C17H17F3N6O [M+H]+: 379. Found: 379.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([Cl:18])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Cl)cc1OC
Temperature: 50 °C

Procedure:
To a suspension of 3-(3,4-dimethoxyphenyl)acrylic acid (416 mg 2 mmol) in toluene (10 mL) was added thionyl chloride (1.45 mL, 20 mmol). The solution was heated at 50° C. for 1 hour and then the solvent was removed under reduced pressure to give (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride, which was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1F
Yield: 76.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.053 g (77%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide as a white solid.