Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[N:3]=[CH:4][N:5]=1
Reactant: c1nc[nH]n1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2cncn2)ncn1
Yield: 76.5 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), 1H-1,2,4-triazole (1.381 g, 20.00 mmol), and cesium carbonate (13.03 g, 40.0 mmol) was stirred in DMF (25 mL) at room temperature for 16 h. The reaction was diluted with 100 mL water and extracted with EtOAc. The combined organic extracts were concentrated and purified by flash chromatography on a 160 g silica gel cartridge with 25 to 50% EtOAc in hexane to yield 4-chloro-6-(1H-1,2,4-triazol-1-yl)pyrimidine (2.78 g, 38% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.21 (1H, s), 8.87 (1H, s), 8.15 (1H, s), 7.91 (1H, s). LCMS: RT=0.68 min, MH+=182.1.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C1COCC1>[CH:1]([CH:5]1[C:2]2([CH2:3][CH2:4][CH2:5][C:1]2=[O:6])[CH2:4]1)=[CH:2][CH3:3]
Reactant: O=C1CCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC=CC1CC12CCCC2=O
Temperature: 25 °C
Yield: 197.3 %

Procedure:
2.1 g (25 mM) of cyclopentanone, containing 0.3% of water, in 20 ml of THF were added dropwise to the reaction mixture while stirring. After having been left for two supplemental hours at reflux and stirring, the reaction mixture was cooled to room temperature, poured onto ice and extracted with ether. The combined organic extracts were successively washed with 1N HCl, a diluted aqueous solution of sodium bicarbonate and finally water. By the evaporation of the volatile components there were obtained 3.7 g of residue which, upon bulb-distillation gave 2.25 g (yield 67%) of the desired spiro-heptanone having a b.p. of 110°-125°/10 Torr. The assessed purity is of about 90%. The product represents an isomeric mixture containing cis- and trans- 1-(prop-1-en-1-yl) spiro [2.4]heptan-4-one in a 2:1 respective weight ratio.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>[OH-].O1CCOCC1>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: Nc1cnc2c(n1)CCNCC2
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Br
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cnc2c(n1)CCN(C(=O)Cc1ccc(Cl)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.8 gm (17.9 mmols) of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide were dissolved in 50 ml of 2N hydroxide, and the solution was admixed dropwise with an ice-cooled solution of 7.5 gm of p-chlorophenyl-acetyl chloride in 50 ml of dioxane. The resulting mixture was stirred overnight and then evaporated, and the residue was extracted with chloroform. The chloroform extract was dried and then evaporated, and the residue was triturated with carbon tetrachloride and suction-filtered.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([F:17])=[C:15]([F:16])[C:9]=2[O:8][CH2:7]1)(=O)C.C(O)C.[OH-].[K+].C(O)(=O)C>O1CCCC1>[F:17][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][CH:6]([CH2:5][OH:4])[CH2:7][O:8][C:9]=2[C:15]=1[F:16]
Reactant: CC(=O)OCC1COc2c(ccc(F)c2F)N1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: OCC1COc2c(ccc(F)c2F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 135 ml of tetrahydrofuran was dissolved 3.03 g of a 3,5-dinitrobenzoyl derivative of (-)-3-acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine, and 135 ml of ethanol and 30 ml of 1.0N potassium hydroxide were added to the solution. After the reaction mixture was stirred at room temperature for 30 minutes, 3 ml of acetic acid was added thereto for neutralization. The mixture was concentrated under reduced pressure, and the concentrate was dissolved in 400 ml of chloroform, washed successively with a sodium bicarbonate aqueous solution and water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The solid was subjected to column chromatography using 40 g of silica gel and eluted with chloroform/methanol (50/1 by volume) to obtain 1.17 g of (-)-7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4H-[1,4]benzoxazine.
Reaction SMILES: N1CCCC(CO)C1.N1CCCCC1CO.[Cl:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]CC)=[O:19]>>[Cl:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Agent: OCC1CCCCN1
Agent: OCC1CCCNC1
Product: CCCCCCCCCCCCCCCCOC(=O)Cl

Procedure:
Following essentially the procedure of Example 1(a), and using in place of 3-piperidinemethanol, an approximately equivalent amount of 2-piperidinemethanol, and using in place of octadecyl chloroformate, an approximately equivalent amount of hexadecyl chloroformate, a white solid was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH2:17][O:18][CH2:19][O:20][CH3:21])([CH2:12][O:13][CH2:14][O:15][CH3:16])C(O)=O)[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([N:31](CC)CC)C.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:31])([CH2:17][O:18][CH2:19][O:20][CH3:21])[CH2:12][O:13][CH2:14][O:15][CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COCOCC(COCOC)(C(=O)O)c1cccc(Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCOCC(N)(COCOC)c1cccc(Br)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a suspension of 2-(6-bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionic acid (18.0 g) in toluene (150 ml)diphenyl phosphoryl azide (4.08 g, 148.27 mmol) and triethylamine (14.97 g [20.6 ml], 148.27 mmol) were added at rt and stirred at 100° C. for 15 h. Reaction mixture was cooled to rt and concentrated under reduced pressure. The residue obtained was dissolved in THF (600 ml) and 20% NaOH solution was added at rt and stirred for 1 h. Solvent was removed under reduced pressure and the product formed was extracted with ethyl acetate. Organic layer was washed with brine, followed by dried over MgSO4. The organic portion was concentrated under reduced pressure and column chromatographic purification of the crude product using 35% ethyl acetate in hexane furnished title compound as a brown liquid. Yield=15.0 g (88% [2 steps]). TLC (70% ethyl acetate in hexane) Rf=0.51; LCMS: RtH7=0.28, [M+1]=335.0 and 337.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][NH:17][CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CNCCCN(C)C
Product: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottom flask at 0° C. was added 4-Bromo-1-fluoro-2-nitrobenzene (10 g, 45.46 mmol) and N,N,N′-Trimethyl-propane-1,3-diamine (6.99 ml, 47.73 mmol). The reaction was allowed to warm to RT and stirred for 16 h. The reaction was extracted into EtOAc, washed once with saturated aqueous NaHCO3, twice with water, and then dried over Mg2SO4. The organic layer was filtered and concentrated to yield the title compound as a bright orange solid.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:2]([C:7]([N:9](C(C2C(C3C=CC=CC=3)=CC=CC=2)=O)[C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].C(O)(=O)C>CO.O1CCCC1>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(N(C(=O)c2ccccc2-c2ccccc2)C(=O)c2ccccc2-c2ccccc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a chilled (0° C.) mixture of 6.0 g of methyl 6-[[bis (2-biphenylcarbonyl)]amino]pyridine-3-carboxylate in 40 ml of methanol and 30 ml of tetrahydrofuran is added slowly 18 ml of 2N NaOH. The mixture is stirred at room temperature overnight and brought to pH 5 with glacial acetic acid. The mixture is concentrated, acidified to pH 2-3 with 1N HCl and extracted with 250 ml of ethyl acetate. The extract is washed with 50 ml of brine, dried (Na2SO4) and the solvent removed under vacuum. The residual white solid is triturated with 15 ml of ethyl acetate to give 3.35 g of white crystals, m.p. 215°-217° C.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:28]([OH:33])/[CH:29]=[CH:30]\[CH2:31][OH:32].CCCCCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[C:1]([O:32][CH2:31][CH:30]=[CH:29][CH2:28][OH:33])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC/C=C\CO
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: OCC=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
Trityl chloride (557 mg; 2 mmol) Et3N (0.306 ml; 2.2 mmol) and DMAP (10 mg; 0.08 mmol) were added to an emulsion of cis-2-buten-1,4-diol (1.76 g; 20 mmol) in DCM (10 ml). The mixture was stirred at room temperature under atmosphere of nitrogen for 24 hours. After such period of time the complete disappearance of trityl chloride was observed by TLC (EtOAC/Hexane 50:50). DCM (20 ml) and water (10 ml) were added to the mixture. The phases were separated and the organic layer was washed with water (10 ml) and brine (10 ml). The solvent was dried over MgSO4 and evaporated under reduced pressure affording a residue (white oil) which was purified by flash chromatography using Hexane/EtOAc 70:30→40:60 as gradient which gave the title product as a colourless oil (563 mg, 81%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:30])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[ClH:31].O1CCOCC1>>[ClH:31].[CH3:1][NH:2][C:3](=[O:30])[C@H:4]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:5][C:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH2:15])[CH2:12][CH2:13]1)=[O:7]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound (III) (2.29 g) was added 4N hydrogen chloride/1,4-dioxane solution (23 ml), and the mixture was stirred at room temperature for one hour. The solvent was evaporated under a reduced pressure, and the residue was washed with ethyl ether and filtered to give N-(trans-4-aminomethylcyclohexylcarbonyl)-L-phenylalanine methylamide hydrochloride (2.03 g) as a white powder.
Reaction SMILES: [Si](O[CH2:9][CH2:10][C:11]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)([CH3:13])[CH3:12])(C(C)(C)C)(C)C.CC1C=CC(S(OC[C@@H]2COC(C)(C)O2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:26][C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]2[CH:22]=[C:14]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][N:15]3[C:16]=2[CH:17]=1
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC1(C)CCn2c1cc1cc([N+](=O)[O-])c(F)cc12
Temperature: 90 °C
Yield: 48.3 %

Procedure:
To a solution of 2-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-6-fluoro-5-nitro-1H-indole (1.9 g, 5.0 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (2.86 g, 10.0 mmol) DMF (10 mL) was added Cs2CO3 (4.88 g, 15.0 mmol). The mixture was heated at 90° C. for 24 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-50% ethyl acetate-hexane) to afford 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole (600 mg, 48%). ESI-MS m/z calc. 248.1, found 249.2 (M+1)+. Retention time 2.00 minutes; 2-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-yl)-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indole (270 mg, containing some (R)-2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-yl)-6-fluoro-5-nitro-1H-indole). ESI-MS m/z calc. 494.2 and 380.2, found 495.4 and 381.4 (M+1)+. Retention time 2.12 and 1.92 minutes; (R)-3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-01 (1.0 g, containing some 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-01). ESI-MS m/z calc. 380.2 and 266.1, found 381.2 and 267.2 (M+1)+. Retention time 1.74 and 1.48 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Reactant: Cc1cc(Br)ccn1
Product: CCN1c2ncc(/C=C/c3ccnc(C)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 83.8 %

Procedure:
By a procedure analogous to that described in Example 51b, 48 mg (0.15 mmol) of 2-chloro-5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one coupled with 4-bromo-2-picoline (31 mg, 0.15 mmol) to provide 51 mg (83%) of the title compound.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].[I-:29].[Na+]>CC(C)=O>[I:29][CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCI
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)propane (1.05 g, 2.53 mmole) in dry acetone (20 ml) was added sodium iodide (1.8 g, 12 mmole) and the mixture was stirred for 36 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed with 10% sodium thiosulfate solution and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 1.04 g=81%.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH3:31])[CH2:10][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 80, 75.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 30.0 mg (40%) of the title compound.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH2:12]([C:18]([NH:20][NH2:21])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16]C>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(=O)NN
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)CCCCC)c2ccccc21
Yield: 32 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and hexanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 32%. 1H NMR (DMSO-d6): δ 0.82-0.91 (m, 6H), 1.27-1.33 (m, 10H), 1.62 (m, 4H), 2.71 (br s, 1H), 3.74 (t, J=7.2 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 12.44 (br s, 1H). 13C NMR (DMSO-d6): δ 14.25 (CH3), 14.29 (CH3), 22.30 (CH2), 22.42 (CH2), 26.33 (CH2), 27.36 (CH2), 31.26 (CH2), 31.28 (CH2), 39.59 (CH2), 110.46 (CH), 119.72 (C), 120.62 (CH), 123.41 (CH), 131.73 (CH), 143.22 (C═N), 161.01 (C═O). HRMS (ES+) calcd for C20H30N3O2 (M+H+), m/e, 344.2335. found, 344.2333.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.O[C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[C:1]1([CH:7]=[CH:8][C:9]([O:11][C:17]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Cc1cccc(C(=O)O)c1O
Solvent: O=S(Cl)Cl
Product: Cc1cccc(C(=O)O)c1OC(=O)C=Cc1ccccc1
Yield: 81.8 %

Procedure:
Using the method of example 4, 14.815 g(0.1 moles) of 3-phenyl-2-propenoic acid and 20.82 g of SOCl2 (0.175 moles) followed by 15.24 g of 2-hydroxy-3-methylbenzoic acid (0.1 moles) give 23.1 g of 2-(3-phenyl-2-propenoyloxy)-3-methylbenzoic acid (yield 81.8%), m.p. 141°-141.5° C.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][NH:22][C@@H:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:20]3)[C:8]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][N:22]([CH3:34])[C@@H:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:20]3)[C:8]3[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Yield: 82.3 %

Procedure:
Combine (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin 1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.259 g, 0.593 mmol), formaldehyde (67 μL, 0.831 mmol, 37%), and sodium triacetoxyborohydride (0.189 g, 0.890 mmol) in dichloroethane (10 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.220 g, 0.488 mmol, 82%) as a yellow oil. Mass spectrum (APCI): m/z=451.3 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine dihydrochloride.
Reaction SMILES: C1(COC([NH:11][C@@H:12]([C:23]([NH:25][C@H:26]([C:39]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)[CH2:43][CH2:42]2)=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=2)=O)C=CC=CC=1.S([O-])(O)(=O)=O.[K+].[H][H]>CO.[Pd]>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([Cl:22])[C:17]=1[OH:21])[CH2:13][C@H:12]([C:23]([NH:25][C@H:26]([C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)[CH2:45][CH2:46]1)=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])=[O:24])[NH2:11]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1cc(Cl)c(O)c(Cl)c1)NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](N)Cc1cc(Cl)c(O)c(Cl)c1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
A solution of 6 g (7.9 mmol) of 1-[N2—[N-[(phenylmethoxy)carbonyl]-3,5-dichloro-D-tyrosyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in a mixture of 200 ml of methanol and 20 ml of aqueous 1 M potassium hydrogen sulphate solution was hydrogenated in the presence of 0.5 g palladium black as catalyst at room temperature under 3 bar of hydrogen pressure for 40 minutes. The catalyst was filtered off, the reaction mixture was evaporated to dryness in vacuo and the residue adjusted to a pH of about 10 by the addition of 2 ml of concentrated aqueous ammonia solution. The product was extracted several times with isopropanol, the combined isopropanol extracts were evaporated down in vacuo and the residue was purified by column chromatography (LiChroprep, Si60 particle size: 20-40 μm, Messrs. Merck (Darmstadt); eluant: methylene chloride/methanol/ammonia=350/75/75/10 (v/v/v/v)). 2.5 g (51% of theory) of a colourless amorphous solid substance were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[C:6]([S:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=O)[CH2:14][CH2:15][O:16]3)=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:29][OH:30]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[C:6]([S:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[N:29][OH:30])[CH2:14][CH2:15][O:16]3)=[CH:11][CH:10]=2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)OCCC4=O)c2)CCOCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)OCCC4=NO)c2)CCOCC1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 7-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]chroman-4-one (0.172 g), hydroxylamine hydrochloride (0.04 g) and pyridine (3 ml) was stirred and heated to 80° C. for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The organic phase was washed with brine, dried (MgSO4) and evaporated. The product was purified by column chromatography using a 4:1 mixture of petroleum ether and ethyl acetate as eluent. There was thus obtained, as a mixture of (E)- and (Z)-isomers, 7-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]chroman-4-one oxime (0.112 g, 63%), m.p. 173°-174° C.;