Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>>[ClH:1].[NH2:7][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[OH:3])[NH:13][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:8]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: N=C(N)c1c(N)cccc1O
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(O)cccc1N2

Procedure:
This was prepared by the method of Example 173 using 2-hydroxy-6-aminobenzamidine dihydrochloride (Example D) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound as a yellow solid, MS (+CI) 305 ([M+H]+), 1H NMR (d6 -DMSO) 11.80 (1H, s), 9.96 (1H, s), 8.64 (1H, s), 8.54 (1H, s), 7.49 (1H, s), 7.23 (1H, t), 6.31 (1H, d), 6.27 (1H, d), 4.02-4.08 (2H, m), 3.5-3.7 (2H, m), 3.3-3.5 (2H, m), 1.6-1.8 (2H, m), 1.19 (3H, t).
Reaction SMILES: C([O:8][CH2:9][C@@:10]12[CH2:19][C:18]([F:21])([F:20])[CH2:17][C@@H:11]1[C:12]([CH2:15][OH:16])=[N:13][O:14]2)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>ClCCl>[F:21][C:18]1([F:20])[CH2:17][C@@H:11]2[C:12]([CH2:15][OH:16])=[N:13][O:14][C@:10]2([CH2:9][OH:8])[CH2:19]1
Reactant: OCC1=NO[C@]2(COCc3ccccc3)CC(F)(F)C[C@H]12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: OCC1=NO[C@]2(CO)CC(F)(F)C[C@H]12
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of rac-((3aR,6aR)-6a-(benzyloxymethyl)-5,5-difluoro-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazol-3-yl)methanol (1.52 g, 5.11 mmol) in dichloromethane (23 ml) was added dropwise at −70° C. boron trichloride (1 M in dichloromethane) (15.3 ml, 15.3 mmol). The reaction mixture was stirred at −70° C. for 1 hour, then allowed to warm to 0° C. within another hour. The reaction mixture was quenched with methanol (10 ml) at −70° C., stirred for 30 minutes at room temperature and evaporated to dryness. The residue was purified by chromatography with a 9:1-mixture of dichloromethane and methanol to give rac-((3aR,6aR)-5,5-difluoro-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,6a-diyl)dimethanol (880 mg, 83% yield) as a light brown solid. MS: m/z=208.1 [M+H]+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1([C:15]([F:22])([F:21])[C:16]([O:18]CC)=O)[C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]1[C:8](=[O:10])[C:7]([F:13])([F:14])[C:2]2([S:1][CH2:6][CH2:5][CH2:4][S:3]2)[C:15]([F:21])([F:22])[C:16]1=[O:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(F)(F)C1(C(F)(F)C(=O)OCC)SCCCS1
Reactant: NCc1ccccc1
Product: O=C1N(Cc2ccccc2)C(=O)C(F)(F)C2(SCCCS2)C1(F)F

Procedure:
React 7.2 mmol of the product of Example 20 with benzylamine using the general procedure set forth in Example 8, and purify by silica gel chromatography using ethyl acetate/hexane as eluant to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([N:17]([CH3:16])[C@H:18]3[CH2:37][N:22]4[C:23]5[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]4[CH2:20][CH2:19]3)=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCCC1
Product: CN(C(=O)C1(c2ccc(Cl)cc2)CCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 1-(4-chlorophenyl)cyclopentanecarbonyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 487.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42])/[C:33](=[N:35]/O)/[NH2:34]>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([C:33]2[N:35]=[C:9]([C:8]3[CH:7]=[CH:6][C:5]([S:1]([NH2:2])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[O:11][N:34]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(S(N)(=O)=O)cc3)n2)cc1Cl
Temperature: 140 °C
Yield: 50 %

Procedure:
To a slurry of 4-sulfamoylbenzoic acid (1.452 g, 7.22 mmol) in DMF (8.20 ml) was added EDC (1.383 g, 7.22 mmol) followed by HOBT hydrate (0.975 g, 7.22 mmol). After about 30 minutes a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide in DMF (8.20 ml) was added. The reaction mixture was heated to about 140° C. for about 2 h. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide (1.28 g, 50%) as a colorless solid. LCMS (Table 1, Method c) Rt=2.74 min, m/z 392 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[BH4-].[Na+]>CC(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.1 %

Procedure:
To a suspension of (E)-1-chloro-4-(4-(2-nitrovinyl)phenoxy)-2-(trifluoromethyl)benzene (13 g, 43.2 mmol) and silica gel (120 g, 100-200 Mesh) in i-PrOH (155 mL) and CHCl3 (465 mL), was added NaBH4 (13.65 g, 361 mmol) portionwise. The reaction mixture was stirred overnight at rt, filtered, and washed with DCM (1 L). The organic phase was washed with sat. NaHCO3 (200 mL), then brine, and dried over anhydrous Na2SO4 and concentrated to afford the title compound as a brown liquid (26 g, 50% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:16]([Cl:15])=[CH:21][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:19][N:18]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A stirred suspension of D7 (5.5 g, 27.5 mmol), 3,6-dichloro-5-trifluoromethylpyridine (3.83 mL, 27.5 mmol) (for synthesis see Tetrahedron, 1985, 41, 4057) and potassium carbonate (11.4 g, 82.6 mmol) in dry N,N-DMF (100 mL) was heated at 120° C. for 24 h. After cooling to ambient temperature, the mixture was poured into water (1 L), stirred for 1 h and then filtered. The residue was washed with water (3×150 mL and dried (MgSO4) to afford the title compound (9.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3,5-dimethylphenyl)acetic acid (2.32 g in 25 mL dry methylene chloride) at 0° C. was added 0.055 mL N,N-dimethylformamide followed by the dropwise addition of 1.3 mL of oxalyl chloride. After 15 minutes the mixture was warmed to room temperature and stiffed for an additional 2 hours. Removal of the solvents in vacuo provided the title compound which was used without purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClC(Cl)C>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-((3-((4-(piperidin-1-yl)-2-(6-((3-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)phenyl)carbamoyl)benzyl)thio)propanoate in 1 mL of dichloroethane was added 1 mL of TFA. The mixture was stirred 1 h, and then the solvent was evaporated. The residue was purified by chromatography on silica gel to give 100 mg of a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.82 (s, 1H), 7.78-7.60 (m, 4H), 7.59-7.50 (m, 4H), 7.45 (t, J=7.6 Hz, 1H), 7.34-7.15 (m, 2H), 6.97 (s, 1H), 4.76 (s, 2H), 3.84 (s, 2H), 3.26 (s, 4H), 2.64-2.54 (m, 2H), 2.53-2.45 (m, 2H), 1.73-1.62 (m, 4H), 1.62-1.50 (m, 2H). MS (ES, m/z): 650.28 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=O.[CH:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:16]/[CH:14]=[O:15]
Reactant: O=CCCCCOC1CCCCO1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C/C=C/CCCCOC1CCCCO1

Procedure:
from 16 g of 5-tetrahydropyranyloxypentanal [E.J. Corey et al., J. Am. Chem. Soc. 92, 6635 (1970)] and 26.1 g of formylmethylenetriphenylphosphorane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([O-])=[O:18].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][OH:18]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)[O-])CC2(CCCOC2)Oc2ccc(Br)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CC2(CCCOC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 6-bromo-4-(tert-butoxycarbonylamino)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-carboxylate (314 mg, 0.69 mmol) in anhydrous THF (10 mL) at −78° C. under N2 atmosphere was added 1 M LAH (in THF, 1.4 mL, 1.4 mmol) dropwise. The mixture was stirred for 30 min at this temperature and then warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and quenched with Na2SO4.H2O carefully, then stirred several hours. The reaction was filtered through a short pad of Celite and washed with THF. The filtrate was evaporated to give 165 mg of the desired product as colorless oil. MS ESI +ve m/z 428 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[C:6]2[C:7](=[O:20])[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:9][CH2:10][N:5]2[N:4]=1.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.FC1C=CC(N2CCN3N=C(COC4C=CC=CN=4)C=C3C2=O)=CC=1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]3[N:4]=[C:3]([CH2:2][O:1][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:21]=[C:6]3[C:7]2=[O:20])=[CH:13][CH:14]=1
Reactant: Clc1ccccn1
Reactant: COc1ccc(CN2CCn3nc(CO)cc3C2=O)cc1
Agent: O=C1c2cc(COc3ccccn3)nn2CCN1c1ccc(F)cc1
Product: COc1ccc(CN2CCn3nc(COc4ccccn4)cc3C2=O)cc1

Procedure:
The compound was prepared from 2-hydroxymethyl-5-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one and 2-chloropyridine using the method described in the preceding example 53 (5-(4-fluoro-phenyl)-2-(pyridin-2-yloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C)c(O)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(Oc2ccc(C)c(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 87.5 %

Procedure:
A mixture of 3-[4-(3-hydroxy-4-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (Example 82, Step J) (1.05 g, 3.34 mmol), 3-bromo-4-fluorobenzotrifluoride (0.81 g, 3.34 mmol) and 325 mesh potassium carbonate (0.55 g, 3.97 mmol) in dry DMSO (15 mL) is heated to 100° C. and stirred for 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 1.57 g (88%) of the title compound. Rf=0.38 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H24O4F3Br 536, found 554 and 556 (M+NH4, 100%).
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:31]C)[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10].[NH4+].[OH-]>O>[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[OH:31])[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10]
Reactant: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCN(CCOc1ccccc1)C1CCc2c(O)cccc2C1

Procedure:
A mixture of pyridine hydrochloride and the product of Example 1 was heated in an oil bath at 200° C. When the reaction was complete (TLC), it was cooled, diluted with H2O, made basic with NH4OH and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (Silica: 8:2 pet ether/EtOAc). The product was dissolved in ether and converted to a hydrochloride salt by the addition of dry ether-HCl. Anal. Calcd. for C21H27NO2 ·HCl: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.54; H, 7.90; N, 3.87. NMR of the free base (300 MHz, CDCl3): δ 7.3-6.6(m, 8H), 4.0(t, 2H), 3.2-2.5(m, 9H), 2.1(m, 1H), 1.7-1.4(m, 3H), 0.9(t, 3H).
Reaction SMILES: [CH:1](/[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=1>CC(N(C)C)=O.[Cu]>[CH:1](/[C:9]1[N:10]([C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=C/c1nc2ccccc2[nH]1)\c1ccccc1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccnc1-n1c(/C=C/c2ccccc2)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 4.6 %

Procedure:
To a stirred solution of (E)-2-styryl-1H-benzimidazole (0.49 g, 2.2 mmol) in dimethylacetamide (20 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (0.11 g, 2.8 mmol). After stirring at 0° C. for 20 min. and then at room temperature for 30 min., a solution of 2-Chloro-3-trifluoromethylpyridine (0.60 g, 3.3 mmol) in dimethylacetamide (5 ml) was added. The resulting mixture was heated to reflux for about 3 h 20 min. After cooling, copper bronze (0.45 g, 7.1 mg-atom) was added and heating was continued for 9 h 20 min. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with dichloromethane (200 ml), washed consecutively with water (3×200 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 150 g; n-hexane/ethyl acetate (2/1)) followed by recrystallization from a mixture of isopropyl ether and n-hexane yielded 37 mg (5%) of the titled compound as white solids. MW: 365.36; mp: 156.0-157.0° C.; 1H-NMR (CDCl3) δ: 8.96 (1H, dd, J=4.8, 1.8 Hz), 8.36 (1H, dd, J=8.1, 1.8 Hz), 7.90 (1H, d, J=15.8 Hz), 7.84 (1H, d, J=8.1 Hz), 7.76 (1H, d, J=8.1, 4.8 Hz), 7.45-7.20 (7H, m), 6.92 (1H, d, J=7.7 Hz), 6.47 (1H, d, J=15.8 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][C:12](OCC)=[O:13])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][CH2:12][OH:13])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[O:4]
Reactant: CCOC(=O)CO[C@@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@@H](OCCO)CN1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 115 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.00 g of the compound obtained in Step 143-1 in THF (40 ml) was added 360 mg of LAH at −40° C., and the reaction mixture was stirred at −10° C. for one hour. To the solution was added sodium sulfate 10 hydrate and the reaction mixture was stirred at room temperature for one hour. The insoluble matter was filtered with celite, the solvent was evaporated under reduced pressure to obtain 2.02 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.Cl[Si:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Si:10]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1
Reactant: CCCC[Si](Cl)(CCCC)CCCC
Reactant: Brc1cccc(Br)c1
Product: CCCC[Si](CCCC)(CCCC)c1cccc(Br)c1

Procedure:
1-Bromo-3-tri-n-butylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chloro-tri-n-butylsilane as the ClSiR1R2R3 compound.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:25]=[CH:24][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].ClC(OCC)=O.O[C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1>ClCCl>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]([O:23][C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=2)=[O:22])=[O:18])=[CH:24][CH:25]=1)([O-:10])=[O:9]
Reactant: O=C(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Oc1ccc(C(=O)O)cc1
Reaction time: 0.33 h

Procedure:
Triethylamine (4 ml) was added to a suspension of N-(4-nitrobenzyloxycarbonyl)glycine (7.25 g) in dry dichloromethane at -20° C. Ethyl chloroformate (2.75 ml) was added to the resultant solution and the mixture stirred at -20° to -10° C. for 20 mins. A solution of 4-hydroxybenzoic acid (3.94 g) and triethylamine (4 ml) in dichloromethane (50 ml) was added dropwise, and stirring continued for 2.5 h after addition. The mixture was filtered, the filtrate washed with 10% aqueous citric acid (20 ml), water (20 ml), and brine (20 ml), and dried (MgSO4). Evaporation under reduced pressure afforded the crude product, 4-[N-(4-nitrobenzyloxycarbonyl)glycyloxy]benzoic acid as a pale yellow foam. Without further purification, 4-[N-(4-nitrobenzyloxycarbonyl)glycyloxy]benzoic acid was treated with chloromethylchlorosulphate (5.77 g) under the conditions described in Example 55b. After work-up and chromatography as described therein, the title compound was obtained as a white crystalline solid (1.81 g), m.p. 119°-120° C. (ethylacetate/hexane); νmax (CH2Cl2) 3450, 1780, 1740, 1610, and 1520 cm-1 ; δH (CDCl3) 4.33 (2H, d, J 6 Hz), 5.33 (2H, s), 5.72 (1H, br t, J 6 Hz), 6.03 (2H, s), 7.23-7.70 (4H, m), and 8.18-8.40 (4H, m).
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS([CH2-])=O.[PH5].[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CS(C)=O.O.C1COCC1>[CH2:3]([OH:2])[CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC=O
Agent: [Br-]
Agent: [CH2-]S(C)=O
Agent: [PH5]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCC/C=C\CCCCCO
Reaction time: 0.33 h

Procedure:
(6-Hydroxyhexyl)triphenylphosphonium bromide 6 (0.5 g, 1.13 mmol) in warm DMSO (3 ml) was added to THF solution of methylsulfinylmethanide ion (prepared from NaH (57 mg, 2.37 mmol) and DMSO (1 ml) under N2 at 70-75° C. for 80 min) with cooling in an ice-bath. The bright yellow solution of phosphorane was stirred at room temperature for 10 min, then treated with octanal (0.159 g, 1.25 mmol) at 0° C. After stirring for 20 min, the reaction mixture was poured into 5 ml H2O and extracted several times with ether. Drying with MgSO4 and concentration affords a residue which was purified by FCC (14% EtOAc in hexanes) to yield 7 (0.13 g, 54%, lit. 60%); δH(270 MHz, CDCl3) 0.86 (3H, t, J=6.5 Hz), 1.10-1.43 (16H, m), 1.55 (2H, m), 2.00 (4H, m), 3.6 (2H, t, J=6.5 Hz) and 5.3-5.4 (2H, m).