Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]([F:12])([F:13])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(C(F)(F)Cl)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(C(F)(F)Cl)nc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanone (B) (0.85 g, 4.14 mmol) in MeOH (10 mL) at 0° C. was added NaBH4 (0.16 g, 4.14 mmol). The mixture was stirred for 30 min and 2 M HCl aqueous solution was added until pH reached 7. Solvent was removed under reduced pressure and the remaining mixture was extracted with CH2Cl2 (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and dried in vacuo to give 0.798 g of analytically pure 1-{6-[chloro(difluoro)methyl]-pyridin-3-yl}ethanol (C) on GC-MS as a light yellow oil in 93% yield. GC-MS: mass calcd for C8H6ClF2NO [M]+ 207. Found 207.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(Cc2cc3c(cn2)OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(Cc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To 1 mL of an ethanol solution containing 80 mg of ethyl 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.25 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 7.5 hours. Further, 0.30 mL of 20% aqueous sodium hydroxide solution was added and left to stand at room temperature overnight. The solvent was removed under reduced pressure, water was added, and adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to give 11 mg of 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylic acid as a white solid. Also, the filtrate was removed under reduced pressure, and the residue thus obtained was purified by reversed-phase silica gel column chromatography [eluent; acetonitrile:water=2:8] to give 31 mg of 1-(2,3-dihydro(1,4)dioxino (2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14]N(C)CC1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:2][CH2:3][N:9]2[CH3:10])[C:2]=1[F:1])=[O:21]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(Nc2cccc(N)c2F)CC1
Solvent: C1COCCO1
Product: CN1CCCCC1Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1F
Yield: 155.8 %

Procedure:
Mix 2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 20) (0.08 g) and 2-chloro-4-fluorobenzoyl chloride (83 mg) in 1,4-dioxane (5 mL) and heat at reflux for 2 hr. Partition the reaction mixture between ethyl acetate and saturated saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (10 g) (dichloromethane-2M NH3 in methanol, gradient) to give 0.106 g of the title compound (78% yield): mass spectrum (ion spray): m/z=380 (M+1); 1H NMR (CDCl3): 8.19 (br s, 1H), 7.83 (dd, 1H), 7.66 (dd, 1H), 7.19 (dd, 1H), 7.09 (ddd, 1H), 7.00 (dd, 1H), 6.52 (ddd, 1H), 3.76 (br d, 1H), 3.29 (m, 1H), 2.81 (br d, 2H), 2.29 (s, 3H), 2.13 (m, 2H), 2.05 (m, 2H), 1.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:17](=O)[CH3:18])[C:14](=[O:16])[CH3:15])=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([CH3:20])[O:7]2.[NH2:22]/[C:23](/[CH3:30])=[CH:24]\[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(O)C>[C:14]([C:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:20])=[CH:5][C:4]3=[O:21])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[NH:22][C:17]=1[CH3:18])(=[O:16])[CH3:15]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1ccc(F)c2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1ccc(F)c2c(=O)cc(C)oc12

Procedure:
150 mg (0.52 mmol) of 3-[(5-fluoro-2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are dissolved with 33.6 mg (0.26 mmol) of ethyl 3-aminocrotonate in 5 ml of 2-propanol and heated under reflux under argon for 3 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: ethyl acetate/cyclohexane 2:1). 50.1 mg (48% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25]>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH3:14]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: COc1ccccc1SC(C(=O)O)C(=O)O
Product: COc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p. 208°-209° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 6.74 (dd, 1H), 6.82 (d, 1H), 6.86 (s, 1H), 6.97 (d, 1H), 7.08 (t, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH2:43])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH:43][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)Cc1cccc(-c2ccccc2N)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cccc(-c2ccccc2NC(=O)CCc2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (61 mg, 0.32 mmol) and Et3N (44 μL, 0.32 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (55 mg, 0.23 mmol) and DMAP (2 mg, 0.02 mmol) and stir the resulting solution for 15 min. Add (2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (71) (50 mg, 0.21 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain {2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-acetic acid methyl ester (72) (46 mg, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3): 2.50 (t, 2H, J=7.6 Hz); 2.90 (t, 2H, J=7.7 Hz); 3.64 (s, 2H); 3.65 (s, 3H); 3.77 (s, 6H); 3.78 (s, 3H); 6.38 (s, 2H); 7.09-7.18 (m, 3H); 7.19-7.28 (m, 3H); 7.34 (d, 1H, J=8.1 Hz); 7.38 (d, 1H, J=7.8 Hz); 8.31 (br.d, 1H, J=7.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][CH:11]1[NH:13][CH2:12]1>C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:10][CH:11]([NH2:13])[CH3:12]
Reactant: CC1CN1
Reactant: Cc1cc(C)cc(O)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(OCC(C)N)c1
Yield: 69107.1 %

Procedure:
24.4 Grams (0.20 mol) of 3,5-dimethylphenol and 3.8 g (0.067 mmol) of propyleneimine in 20 ml of toluene were allowed to react in an autoclave at 10 kg/cm2G at 200° C. for 1 hour. The reaction product was dispersed in 50 ml of ether, and then subjected to extraction with 50 ml of 5% hydrochloric acid three times. The water layer of the product was neutralized with sodium hydroxide, and the product was subjected to extraction with 50 ml of ether three times. The ether layer was washed and dried. Then, ether was distilled off, and the residue was distilled under reduced pressure to give 8.3 g of 1-(3,5-dimethylphenoxy)-2-propylamine as a component having a boiling point of 87° to 89° C./0.3 mmHg. Its yield was as high as 70%.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:29].C([O-])(O)=O.[Na+]>>[CH3:19][C:16]1([CH3:20])[O:15][CH:14]([CH2:13][N:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:29])[C:7]2=[O:12])[CH2:18][O:17]1
Reactant: CC1(C)OCC(Cn2ccc3c(N)cccc3c2=O)O1
Reactant: I
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)OCC(Cn2ccc3c(I)cccc3c2=O)O1
Reaction time: 1 h

Procedure:
5-Amino-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)isoquinolin-1(2H)-one (4.2 g, 0.015 mol) was added to a solution of sodium nitrite (4 g, 0.06 mol) in dimethyl sulfoxide (80 mL, 1 mol) at 35° C. Aqueous hydrogen iodide (8 mL, 0.06 mol) in dimethyl sulfoxide (80 mL, 1 mol) was added, and the reaction mixture was stirred for 1 hour. The cooled reaction mixture was neutralized with sat. aq. NaHCO3 and extracted with methylene chloride (3×50 mL). The combined methylene chloride extracts were washed with brine, dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified via flash column chromatography (40 g of silica gel, 0-50% EtOAc/Hexane) to give a light yellow solid. MS m/z (M+H) 385.6
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][N:26]([CH3:33])[C:27]2=[O:32]>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][N:26]([CH3:33])[C:27]3=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2c(=O)n(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 295 mg (1.0 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 217 mg (1.0 mmol) of 5-amino-2-methylphthalazin-1-one and 0.53 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentyliden]amino}-2-methylphthalazin-1-one. 590 mg of resultant crude imine are cyclized, in the same way as in Example 1, at −30° C. using 10 ml (10 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-60%) yields 204 mg of product.
Reaction SMILES: CC1(C)OC(=O)[CH:5]([C:9]([CH3:26])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH2:10][CH3:11])[C:4](=[O:27])[O:3]1>CN(C=O)C.O.Cl>[CH3:26][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)([CH2:10][CH3:11])[CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCC(C)(c1cccc(OCc2ccccc2)c1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(CC(=O)O)c1cccc(OCc2ccccc2)c1
Yield: 65.3 %

Procedure:
A solution of 5-(2-(3-(benzyloxy)phenyl)butan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione 103.C (209 mg, 546 μmol) in DMF (2 mL) and H2O (0.2 mL) was heated to 90° C. overnight. The reaction was then diluted with 0.2N HCl, extracted with EtOAc, dried over MgSO4, filtered, stripped, and purified by silica gel chromatography to afford 3-(3-(benzyloxy)phenyl)-3-methylpentanoic acid 103.D (106.4 mg, 65.3% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:15]([CH:17]([CH:19]([C:29]([NH2:31])=[O:30])[C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH3:18])[CH:16]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:15]([CH:17]([CH:19]([C:29]([NH2:31])=[O:30])[C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH3:18])[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(c1cc(N)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(c1cc(NC(=O)c2ccccc2)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reaction time: 2 h

Procedure:
An amount of 0.30 ml (2.62 m mol) of benzoyl chloride was added dropwise to a solution of 1 gm (2.62 m mol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and of 0.37 ml (2.62 m mol) of triethylamine in 10 ml of anhydrous dimethyl formamide. After stirring for two hours at 20° to 30° C., the reaction mixture was evaporated in vacuo and distributed between water and ethyl acetate. The organic phase was dried, filtered, and evaporated in vacuo. The evaporation residue (1.12 gm) was recrystallized from ethanol by addition of activated charcoal.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[CH3:27][NH2:28].O>CN(C)C=O>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH:15]1[CH2:14][C:13](=[O:26])[CH2:12][CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:28]1[CH3:27]
Reactant: O=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1
Reactant: CN
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(c2ccc3ccccc3c2)CC(=O)CC1c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
1,5-Bis(2-naphthyl)-1,4-pentadien-3-one (25, 0.82 g, 2.5 mmol) was dissolved in dimethyl formamide (15 ml). Methylamine (51, 1.30 ml, 15.1 mmol, 40% in water) was added and the mixture stirred for 72 hr at room temperature. The mixture was poured into water (100 ml) and stirred for 24 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized twice from ethanol to give 0.20 g (22%) of a white solid: mp 209-212° C.; 1H NMR δ 1.89 (s, 3H), 2.59 (d, 2H, J=13.9 Hz), 2.97 (t, 2H, J=11.3 Hz), 3.66 (d, 2H, J=11.7 Hz), 7.49 (m, 4H), 7.81 (m, 10H); 13C NMR: δ 41.1, 50.7, 70.3, 124.6, 125.9, 126.0, 126.2, 127.6, 127.7, 128.9, 133.0, 133.4, 140.4, 206.6; Exact mass calcd for C26H23NO: 365.1780, observed (M+H) 366.1852.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:16](Cl)(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([NH:24][S:16]([C:4]1[CH:5]=[CH:6][C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1)(=[O:18])=[O:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1NS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 34.3 %

Procedure:
3-Methyl-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) was added to tetrahydrofuran (40 ml) containing t-butylamine (0.65 g), and the resultant mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated and extracted with chloroform. The extract was washed with 5% hydrochloric acid and water in order, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from benzene and then from toluene to give 0.57 g of N-t-butyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 139.5°-140.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][C@H:6]([NH:20]C(=O)OC(C)(C)C)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:20][C@@H:6]([CH2:5][C:4]1[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reaction time: 1 h

Procedure:
tert-Butyl (1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate (VII, EXAMPLE 4, 258 mg, 0.59 mmol) is dissolved in methylene chloride (1 mL) at 20-25 degrees C., and trifluoroacetic acid (1 mL) is added with stirring under nitrogen. The reaction mixture is stirred at 20-25 degrees C. for 1 hour, whereupon the reaction mixture is concentrated under reduced pressure to give the title compound. The title compound is used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: Fc1ccc(Br)c(CBr)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(F)ccc1Br
Yield: 95 %

Procedure:
Compound 15.2 was prepared as described for example 6.2 by reacting compound 1.1 with 2-bromo-5-fluorobenzyl bromide. 4-[3-(2-Bromo-5-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 95% (molecular weight 483.02 (C20H14BrF4N3O2); retention time Rt=2.10 min. [B]; MS (ESI): 484.26 (MH+)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1>>[Br:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ccc(Br)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(Br)ccc2n1
Yield: 42 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-5-bromopyridine instead of 2-aminopyridine, to the title compound (75 mg, 42%) which was obtained as a yellow gum. MS: m/e=354.1/356.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9](=S)[NH:10][C:4]=2[CH:3]=1.[CH2:23]([N:26]([CH2:30][C:31]([NH:33][NH2:34])=O)[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(O)CCC>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9]3[N:10]([C:31]([CH2:30][N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[N:33][N:34]=3)[C:4]=2[CH:3]=1
Reactant: CCCN(CCC)CC(=O)NN
Reactant: Cc1ccc2c(c1)NC(=S)CN=C2c1ccc(C(C)C)cc1
Solvent: CCCCO
Product: CCCN(CCC)Cc1nnc2n1-c1cc(C)ccc1C(c1ccc(C(C)C)cc1)=NC2

Procedure:
In the manner given in Example 5, a solution of 1,3-dihydro-8-methyl-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to a reflux with (dipropylamino)acetic acid hydrazide to give 9-methyl-1-[(dipropylamino)methyl]-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4)benzodiazepine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@:6]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:11]([O:12][C@@H:13]2[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]2[O:15][C:16](=[O:18])[CH3:17])[C@H:9]([OH:10])[C@H:8]1[NH:44][C:45](=[O:47])[CH3:46])[OH:7].S1C=CC=C1[C@@:53]1([O:83][C@@H:82]([CH3:84])[C@@H:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@@H:64]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C@@H:55]1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)O.[Sn](Cl)Cl>C(OCC)C.Cl([O-])(=O)(=O)=O.[Ag+]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@:6]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:11]([O:12][C@@H:13]2[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]2[O:15][C:16](=[O:18])[CH3:17])[C@H:9]([OH:10])[C@@:8]1([C@@H:53]1[O:83][C@@H:82]([CH3:84])[C@@H:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@@H:64]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C@@H:55]1[O:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[NH:44][C:45](=[O:47])[CH3:46])[OH:7]
Reactant: C[C@@H]1O[C@@](O)(c2cccs2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@@H](CO)O[C@]1(O)c1cccs1
Agent: [Ag+]
Agent: Cl[Sn]Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Product: CC(=O)N[C@]1([C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@@H](CO)O[C@]1(O)c1cccs1

Procedure:
Compound [13] (0.2-4.81 g, 0.234-5.78 mmol) is dissolved with compound [17] (0.17-4.15 g, 0.37-9.25 mmol) in dry diethyl ether (5-100 ml) and stirred with 4 Å molecular sieves (0.1-6.8 g), silver perchlorate (0.15-3.59 g 0.702-17.34 mmol) and tin(II) chloride (0.13-3.29 g, 0.702-17.34 mmol) until the reaction is complete. The mixture is subsequently filtered, and the crude product compound [18] obtained after concentration is purified by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.25-6.2 g, 0.2-4.91 mmol, about 85% yield). FAB-MS: M+H+ =1262. NMR data consistent with Nicolaou et al., J. Am. Chem. Soc. 114:3127 (1992) and C. W. Hummel, Ph.D. Dissertation, University of California, San Diego (1993).