Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]([C:17]1[C:21](O)([CH3:22])[O:20][C:19](=[O:24])[CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>COCCOC>[OH:3][CH:4]([C:17]1[CH:21]([CH3:22])[O:20][C:19](=[O:24])[CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCC(O)C1=CC(=O)OC1(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCC(O)C1=CC(=O)OC1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
NaBH4 (210 mg, 5.54 mmol) was added in portions to a solution of 4-(1-hydroxytridecyl)-5-hydroxy-5-methyl-2-furanone (586 mg, 1.85 mmol) in anhydrous ethyle glycol dimethyl ether (60 mL) at 0° C. under argon. After stirring for 3 hours at 0° C. the reaction was quenched with HCl (6N) to pH2 and extracted with ethyl acetate. The combined organic fractions were washed with a saturated solution of aqueous sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 30% ethyl acetate/hexane to give the title compound as a mixture of diastereomers. Recrystallization from diethyl ether/hexane gave a single diastereomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a solution of ethyl 4-(1-tert-butoxycarbonylpiperidin4-yloxy)-phenoxyacetate (23.71 g) in a mire of tetrahydrofuran (34 ml) and ethanol (34 ml) was dropwise added 1N aqueous lithium hydroxide solution (68.7 ml) with ice-cooling, and the mixture was stirred at room temperature for 20 min. After completion of the reaction, the solvent was evaporated and to the obtained residue was added 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained solid was filtrated with hexane and dried under reduced pressure to give the title compound (19.09 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 51.3 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.45 g) and sodium bicarbonate (0.63 g) in water (5 ml) was stirred at ambient temperature for 7 days. The reaction mixture was adjusted to pH 6.0 with acetic acid. The solution was subjected to column chromatography on macroporous nonionic adsorption resin "Diaion HP-20" (30 ml) and eluted with water. The eluate was acidified to pH 2.2 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g), which was identified by comparing the physico-chemical data with those of the object compound in Example 90.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:14]([Cu])#[N:15].[C-]#N.[K+].C(Cl)(Cl)Cl>CN(C=O)C.CCOC(C)=O>[C:14]([C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)#[N:15]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ccc2c1
Agent: [C-]#N
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Yield: 78.8 %

Procedure:
A solution of 7-bromo-5-nitroindole (2.5 g, 10.4 mmol), CuCN (3.0 g, 33.3 mmol) and KCN (3.0 g, 46.1 mmol) in 20 mL of DMF was stirred at 120° C. for 24 h. The reaction mixture was diluted with 500 mL of EtOAc and washed with brine several times. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding a brown oily residue which was subjected to column chromatography (CHCl3, neat) to provide 1.5 g (8.2 mmol, 77%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[C:10]([CH3:9])=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccnc(Cl)n1
Product: Cc1c(C=O)cccc1-c1ccnc(Cl)n1
Yield: 50 %

Procedure:
2,4 dichloropyrimidine and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was coupled following procedure A. The yield was 50%. LC-MS showed the product was >95% pure and had the expected M+H+ of 233. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.9 (s, 1H) 8.6 (s, 1H) 7.5 (d, 2H) 7.4 (t, 1H), 7.2 (d, 1H), 2.5 (s, 3H).
Reaction SMILES: [H-].[K+].[C:3]([O:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][OH:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:22](Br)[CH:23]=[CH2:24]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][O:21][CH2:24][CH:23]=[CH2:22])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CC(CO)Cc2ccccc21
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCOCC1Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
0.5 g of a potassium hydride suspension (20% in oil) is added to a solution of 0.6 g of 1-tert-butoxycarbonyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline in 7 ml of tetrahydrofuran at 0° C., the mixture is stirred for 30 min and 0.58 ml of allyl bromide is then added. After the mixture has been stirred at 0° C. for 45 min, it is worked up in the customary manner and the crude product is purified over 50 g of silica gel (mobile phase F). 1-Tert-butoxycarbonyl-3(R,S)-allyloxymethyl-1,2,3,4-tetrahydroquinoline is obtained as a colourless oil (Rf (F)=0.40), which is then reacted analogously to Example 20a). Purification by means of FC over 50 g of silica gel with methylene chloride as the mobile phase gives 3(R,S)-allyloxymethyl-1,2,3,4-tetrahydroquinoline: Rf (F)=0.40; MS: M+ =203.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:54])[NH:15][C@@H:16]([C:28](=[O:53])[N:29]([C@@H:31]([C:43]2[O:47][N:46]=[C:45]([C:48]([O:50]CC)=[O:49])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:54])[NH:15][CH:16]([C:28](=[O:53])[N:29]([CH:31]([C:43]2[O:47][N:46]=[C:45]([C:48]([OH:50])=[O:49])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)C(Cc1ccc2ccccc2c1)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1)C(Cc1ccc2ccccc2c1)c1nc(C(=O)O)no1
Yield: 54.8 %

Procedure:
4-((1R)-1-{[(1R)-1-(3-Ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (0.79 g, 1.06 mmol) was dissolved in dioxane (5.5 ml). Water (3 ml) and solid lithium hydroxide (0.03 g) was added. After 18 h at 20° C. the reaction mixture was diluted with water (15 ml) and extracted with tert-butyl-methylether (2×10 ml). The aqueous phase was acidified with 1N aqueous sodium hydrogenphosphate (2.5 ml) and extracted with tert-butyl-methylether (3×40 ml). The collected organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was chromatographed on silica (60 g) using a mixture of dichloromethane and 10% ammonia in ethanol (4:1) as eluent to give 0.41 g of 4-(1-{[1-(3-carboxy-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)-ethylcarbamoyl)piperidine-1-carboxylic acid tert-butylester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:40]=[CH:39][C:22]([NH:23][C:24]2[CH:36]=[C:35]([CH:37]=[CH2:38])[CH:34]=[CH:33][C:25]=2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:18][C:19]1[CH:40]=[CH:39][C:22]([NH:23][C:24]2[CH:36]=[C:35](/[CH:37]=[CH:38]/[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[CH:34]=[CH:33][C:25]=2[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
1-Bromo-4-(trifluoromethyl)benzene 0.14 mL, cesium carbonate 0.31 g and palladium acetate 11 mg were added to N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.15 g at room temperature, and it was stirred at 120° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(4-trifluoromethylphenyl)vinyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1(O)[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH:10]=1
Reactant: COc1ccccc1C1(O)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C1=CCC(=O)CC1
Temperature: 80 °C

Procedure:
To a solution of 8-(2-Methoxy-phenyl)-1,4-dioxaspiro[4.5]decan-8-ol (100 mg, 0.379 mmol) in 10 mL THF was added HCl (1.4 mL 6M, 8.4 mmol). The solution was heated to 80° C. for 45 min, then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica (dichloromethane/3% methanol as eluent) to give 4-(2-Methoxy-phenyl)-cyclohex-3-enone
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.C[Mg]I.O.Cl>C1(C)C(C)=CC=CC=1.C(OCC)C>[OH:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:6]=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=2)=[CH:12][CH:13]=1
Reactant: COc1cc(OC)cc(-c2ccc(CCO)cc2)c1
Agent: C[Mg]I
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCOCC
Solvent: O
Product: OCCc1ccc(-c2cc(O)cc(O)c2)cc1

Procedure:
17.0 g (65.2 mmol) of 2-(3′,5′-dimethoxybiphenyl-4-yl)ethanol are dissolved in 1 l of xylene, and, after addition of 110 ml (330 mmol) of a 3 M solution of methylmagnesium iodide in diethyl ether, the mixture is heated under reflux for 3 d. The batch is subsequently carefully hydrolysed by addition of water and acidified using dil. hydrochloric acid. The org. phase is separated off, washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is recrystallised from toluene, giving 4′-(2-hydroxyethyl)biphenyl-3,5-diol as a colourless solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]2[CH2:61][CH2:60][N:59]([CH2:62][C:63]([NH2:65])=[O:64])[CH2:58][CH2:57]2)=[CH:52][C:51]=1[O:66][CH3:67]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:49][C:50]4[CH:55]=[CH:54][C:53]([CH:56]5[CH2:61][CH2:60][N:59]([CH2:62][C:63]([NH2:65])=[O:64])[CH2:58][CH2:57]5)=[CH:52][C:51]=4[O:66][CH3:67])=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (127.4 mg, 0.368 mmol) and N,N-Diisopropylethylamine (0.257 mL, 1.47 mmol) in 3.2 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (113 mg, 0.318 mmol). After stirring at room temperature for 1 hour, 2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetamide (92 mg, 0.349 mmol) was added. The reaction mixture was heated at 65° C. overnight. The reaction was conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using DCM then 500:15:10 DCM:MeOH:7N NH3/MeOH as the eluant. The collected fractions afforded 2-(4-{4-[7-(3-tert-Butylsulfamoylphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxyphenyl)piperidin-1-yl)-acetamide as a yellow solid (23.0 mg, 11%). MP 250-252° C. LCMS (E/I+) 592.25 (M+H). 1H NMR (DMSO-d6)-9.02 (s, 1H), 8.55 (s, 1H), 8.37 (d, 1H, J=7.84 Hz), 7.99 (d, 1H, J=7.96 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.69 (t, 1H, J=7.86 Hz), 7.63 (s, 1H), 7.23 (d, 1H, J=4.80 Hz), 7.21 (br s, 1H), 7.15 (br s, 1H), 7.01 (d, 1H, J=4.72 Hz), 6.95 (s, 1H), 6.92 (s, 1H), 3.88 (s, 3H), 2.97-2.90 (m, 2H), 2.88 (s, 2H), 2.49-2.41 (m, 1H), 2.22-2.11 (m, 2H), 1.84-1.72 (m, 4H), 1.12 (s, 9H).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36]>O1CCOCC1>[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:34]([CH3:39])([C:35](=[O:36])[NH2:37])[CH3:38])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(Br)C(N)=O
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OC(C)(C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Sodium hydride (10.8 mg of a 60% dispersion in oil, 0.27 mmol) was added to a solution of the phenol prepared in example 91 (100 mg, 0.25 mmol) in dry dioxane (1 ml) and the mixture stirred for 1 h at room temperature. 2-Bromo-2-methylpropanamide (Coutts, I. G. C., Southcott, M. R. J. Chem. Soc. Perkin Trans. 1, 1990, 767) was then added and the mixture heated at 100° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo, and purified by flash chromatography (1:1 ethyl acetate: hexanes) to afford a light yellow solid (94.4 mg, 94%). MS (FD+) 489.6, Mp 84–86° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[C:9]1([C:15](=[N:22][NH2:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[C:15](=[N:22]/[N:23]=[CH:7]/[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1sccc1Br
Reactant: NN=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: Brc1ccsc1/C=N/N=C(c1ccccc1)c1ccccc1
Temperature: 65 °C
Yield: 102 %

Procedure:
To a solution of 3-bromothiophene-2-carbaldehyde (5.57 g, 29.2 mmol) in EtOH (90 mL) was added (diphenylmethylene)hydrazine (6.3 g, 32.1 mmol). The reaction mixture was heated at 65° C. for 4 h then concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane to afford 11 g of N-benzhydrylidene-N′-[1-(3-bromo-thiophen-2-yl)-meth-(E)-ylidene]-hydrazine as a viscous yellow oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](Br)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: CN1CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: CN1CCN(c2nnc3n2-c2ccc(C(F)(F)F)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 8-(trifluoromethyl)-1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-(trifluoromethyl)-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O[N:14]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.CO>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[O:1]1[C:5]2[C:6]([C:10]([NH2:14])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
2,3-Dihydrobenzofuran-7-carboxylic acid (15.0 g, 91 mmol) was dissolved in DCM (150 ml) and DMF (150 ml). 1-Hydroxybenzotriazole (12.3 g, 91 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (17.5 g, 91 mmol) was added. The reaction mixture was stirred for 20 min at 0° C. A 1 N solution of ammonia in methanol (200 ml, 200 mmol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with a 10% aqueous sodium hydrogensulphate solution. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (400 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The remaining crystals were washed with ethyl acetate (3×100 ml) and dried in vacuo to give 5.21 g of 2,3-dihydrobenzofuran-7-carboxylic acid amide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][CH2:18][OH:19].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC.[CH3:51][O:52][C:53](=[O:65])[CH2:54][C:55]1[C:59]2[CH:60]=[CH:61][C:62](O)=[CH:63][C:58]=2[O:57][CH:56]=1>C1(C)C=CC=CC=1.O>[CH3:51][O:52][C:53](=[O:65])[CH2:54][C:55]1[C:59]2[CH:60]=[CH:61][C:62]([O:19][CH2:18][CH2:17][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=4)[S:6][C:2]=3[CH3:1])=[CH:63][C:58]=2[O:57][CH:56]=1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1coc2cc(OCCc3nc(-c4ccc(C(F)(F)F)cc4)sc3C)ccc12
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution of 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (0.12 g, 0.43 mmol) in toluene (3 mL) at 0° C. is added ADDP (0.14 g, 0.57 mmol) followed by tri-n-butylphosphine (0.14 mL, 0.56 mmol). A toluene solution of (6-Hydroxy-benzofuran-3-yl)-acetic acid methyl ester (0.52 g, 1.22 mmol) is added, and the mixture is allowed to warm to RT overnight. Water is added, and the aqueous phase is extracted with EtOAc. The organics are dried with MgSO4 and purified by flash chromatography to yield the title compound (0.066 g, 33%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1>CN(C=O)C>[CH2:3]([O:10][C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3ccc(OCCCN4CCCCC4)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
Sodium hydride (0.007 g, 0.18 mmol) was stirred in anhydrous DMF (4 mL) under a nitrogen atmosphere, and benzyl alcohol (0.016 g, 0.15 mmol) was added. After 15 min., 3-chloro-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyridazine (0.05 g, 0.15 mmol) was introduced, and the reaction mixture was stirred at room temperature for 5 h. The precipitate was collected by filtration, washed with H2O (10 mL) and dried in vacuo to provide the title compound as a white solid (0.050 g, 83%), m.p. 138° C.; 1H NMR (CDCl3) 2.00 (m, 2H, —CH2—), 2.50 (m, 2H, —CH2—), 4.10 (m, 2H, —CH2—), 7.00 (d, 1H, C—H), 7.05 (d, 2H, Ar—H), 7.75 (d, 1H, C—H), 7.95 (d, 2H, Ar—H) HPLC retention time 2.612 mina.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:27])[N:8]([CH2:9][CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][CH2:13][OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCCC(C)(C)CCO
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: CCCCCCCN(CCC(C)(C)CCO)C(=O)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
Part C. A solution of the amine prepared in Part C (4.26 g, 18.6 mmol) in methylene chloride (20 mL) was cooled to 0° C., and a solution of 2,4-difluorophenyl isocyanate (2.20 mL, 18.6 mmol) in methylene chloride (20 mL) was added dropwise with stirring over 1 hour. After slow warming to ambient temperature over 18 hours, the reaction mixture was concentrated under vacuum, and the residual oil was purified by flash chromatography to afford N'-(2,4-difluorophenyl)-N-(3,3-dimethyl-5-hydroxypentyl)-N-heptylurea as a colorless oil (2.31 g, 6.01 mmol, 32%). 1H NMR (CDCl3) δ7.93(br q,1H,J=6.2Hz); 6.89-6.78(m,3H); 3.76(t,2H,J=6.3Hz); 3.38-3.24(m,4H); 2.36(br s,1H); 1.65-1.52(m,6H); 1.36-1.24(m,8H); 0.97(s,6H); 0.89(t,3H,J=6.6Hz).