Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[S:15][C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH:22]([CH3:24])[CH3:23].Cl>C(Cl)Cl>[CH3:23][CH:22]([C:18]1[S:17][C:16]([C:14]2[S:15][C:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:12][CH:13]=2)=[CH:20][CH:19]=1)[CH3:24]
Reactant: c1ccc(-c2ccc(-c3cccs3)s2)cc1
Reactant: CC(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(-c2ccc(-c3ccccc3)s2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A stirred suspension of 0.55 gram (0.0041 mole) of aluminum chloride in 40 ml of methylene chloride was cooled to 0° C., and a solution of 1.0 gram (0.0041 mole) of 5-phenyl[2,2'-bithienyl], 0.9 gram (0.005 mole) of 2-chloropropane in 40 ml of methylene chloride was added dropwise. Upon completion of addition the reaction mixture stirred at 0° C. for 30 minutes, then was allowed to warm to ambient temperature where it stirred for 16 hours. The reaction mixture was poured into a mixture of ice and aqueous 10% hydrochloric acid. The layers were separated and the aqueous phase was extracted with three 25 ml portions of diethyl ether. The organic layers were combined and the combination washed in succession with a solution of aqueous 5% sodium bicarbonate, water, and an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with 100% hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.7 gram of 5'-(1-methylethyl)-5-phenyl[2,2'-bithienyl]; m.p. 104°-106° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]#[CH:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]#[C:33][C:2]2[C:3](=[O:18])[N:4]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH:5]=[C:6]([Cl:8])[N:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(Cl)nc(C#CC3CCN(C(=O)OC(C)(C)C)CC3)c2=O)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3,5-dichloro-1-(4-methoxy-benzyl)-1H-pyrazin-2-one (285 mg; for preparation see Tetrahedron Letters 2010, 51, 1739) and 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (272 mg), triethylamine (2 mL) and N,N-dimethylformamide (2 mL) in a microwave oven suited vessel charged with a stir bar is sparged with argon for 10 min. Copper (I) iodide (8 mg) and Pd(PPh3)2Cl2 (10 mg) are added and the vessel is capped. The resulting mixture is stirred under microwave irradiation at 80° C. for 15 min. After cooling the mixture to room temperature, ethyl acetate is added. The organic phase is washed with 2 N aqueous citric acid, water, and brine, dried (MgSO4) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 40:60) to give the title compound. Yield: 440 mg (96% of theory); LC (method 2): tR=1.47 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[C:7]([F:32])[CH2:6]1)C.CN.CC(O)=O>>[CH3:1][NH:2][N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[C:7]([F:32])[CH2:6]1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2)=C(F)C1
Agent: CN
Solvent: CC(=O)O
Product: CNN=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2)=C(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.284 mmol) from EXAMPLE 33, a pre-mixed methylamine (2M in THF, 0.713 mL, 1.43 mmol) and HOAc (0.122 mL, 2.14 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (18 mg). MS 454.1 and 456.1 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1)(=[O:5])=[O:4].O1CC[CH2:19]OO1>CS(O)(=O)=O.FC(F)(F)C(O)=O>[F:15][C:13]1[CH:12]=[CH:11][C:8]2=[C:7]3[C:14]=1[CH2:1][N:2]([CH3:19])[S:3](=[O:4])(=[O:5])[C:6]3=[CH:10][S:9]2
Reactant: CNS(=O)(=O)c1csc2ccc(F)cc12
Reactant: C1COOOC1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(F)ccc3scc(c23)S1(=O)=O
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
0.37 g of 5-fluoro-benzo[b]thiophene-3-sulphonic acid-methylamide are dissolved in 5.9 ml of methanesulphonic acid at 35° C. and combined with a solution of 0.06 g of trioxane in 1.8 ml of trifluoroacetic acid. After 2.5 h stirring at 35° C. the reaction mixture is poured onto 100 ml of ice water and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried with Na2SO4, evaporated down in vacuo and then purified by chromatography. Yield: 0.22 g. M.p.: 175° C.
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)[Cl:3].[CH3:6][CH:7]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][Mg]Br>O1CCCC1>[CH3:6][CH:7]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][Si:2]([Cl:5])([Cl:3])[Cl:1]
Reactant: CC(C)CCCC(C)CC[Mg]Br
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Tetrahydrofuran (100 ml) and tetrachlorosilane (17.0 g, 100 mmol) were placed in a 500 mL four-necked flask in a nitrogen atmosphere, and cooled to −10° C. 3,7-dimethyloctyl magnesium bromide (Sigma-Aldrich Co. LLC., 1.0 M, 100 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was distilled under reduced pressure to obtain the target 3,7-dimethyloctyl trichlorosilane (99-102° C./0.3 Torr, 22.3 g, yield 81%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][C:18]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CC)CC)C.[O-][Si]([O-])=O.[Mg+2]>CCCCCC.C(OCC)(=O)C.CCCCCC>[CH3:17][C:18]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:19]=1[C:20]([C:6]1[N:2]([CH3:1])[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:5]=1)=[O:21]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc([N+](=O)[O-])cc3)n2C)c(C)c1
Reaction time: 48 h
Yield: 42.3 %

Procedure:
4-(1-Methylpyrrol-2-ylmethyl)nitrobenzene (1.2 g, 5.5 mmol) [prepared as in Example 7, Step (b)], 2,4-dimethylbenzoyl chloride (1.6 g, 9.5 mmol), and triethylamine (1.3 ml, 9.3 mmol) were dissolved in xylenes (50 ml), and the reaction mixture was heated at reflux under argon. After 48 h, the reaction mixture was passed through a Florisil® column (hexane followed by hexane-ethyl acetate, 95:5) to give 4-{5-(2,4-dimethylbenzoyl)-1-methyl-1H-pyrrol-2-yl-methyl}nitrobenzene (0.81 g, 42%) as a solid. ##STR41##
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]C1CCCCO1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH:3]=[C:2]([CH3:21])[CH3:1]
Reactant: COC(=O)c1ccc(OC2CCCCO2)c(C=C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1ccc(O)c(C=C(C)C)c1
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a stirred mixture of 66.20A (0.460 g, 2 mmol) in MeOH (8 mL) was added PPTS (0.04 g, 0.2 mmol). The reaction mixture was then stirred for 24 hours and then concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield 66.20B as a colorless oil (0.320 g, 98% yield).
Reaction SMILES: [CH2:1]([N:7]1[C:12](=O)[CH:11]2[CH:9]([C:10]2([CH:23]([CH3:25])[CH3:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O1CCCC1.B.CO>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH:23]([CH3:24])[CH3:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCN1CC2C(C1)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Preparation 59, 0.57 g, 1.6 mmol) in tetrahydrofuran (6 ml), under nitrogen, was added borane tetrahydrofuran complex (1M in tetrahydrofuran, 3.0 ml, 3.0 mmol) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was cooled to room temperature before the addition of further borane tetrahydrofuran complex (1M in tetrahydrofuran, 3.0 ml, 3.0 mmol). After 20 min, the reaction mixture was cooled to room temperature and methanol (8 ml) was added and then the reaction mixture was once more heated under reflux for 6 h. The reaction mixture was concentrated in vacuo and the residue was dried under vacuum at room temperature. The residue was treated with dichloromethane (4 ml), filtered and purified by chromatography on a Biotage Flash40S™ cartridge packed with silica gel (40 g) eluting with hexane:ethyl acetate (6:1). The title compound was obtained initially as a yellow oil which crystallised upon standing (0.2 g, 40%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.215 ml 2-(3-chloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 4 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 465 mg light yellow oil (100%). MS (ISP) 302.3 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:6]1([CH3:9])[CH2:7][CH:2]([NH:1][C:12](=[O:14])[CH3:13])[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)NC1CC(C)(C)NC(C)(C)C1
Reaction time: 0.5 h
Yield: 874.6 %

Procedure:
A solution of 100.0 grams (64 mmol) of 4-amino-2,2,6,6-tetramethylpiperidine in 150 ml of toluene and a solution of 65.4 grams (64 mmol) of acetic anhydride in 175 ml of toluene are simultaneously added over a 45-minute period to a flask containing 150 ml of toluene. The reaction temperature is maintained at 25°-35° C. by using an ice water bath. The reaction mixture is stirred for 30 minutes after the addition is complete. Solids are separated by filtration, washed with ether and dissolved in 500 ml of water. This aqueous solution is added to a solution of 28 grams of sodium hydroxide in 100 ml of water. A crude solid is isolated by filtration and the filtrate is saturated with solid sodium chloride to precipitate more of the product. The solids are combined, dried and dissolved in warm isopropanol. The alcohol solution is filtered to remove salts, and the filtrate is concentrated to give an oil. The oil is crystallized from heptane to afford 111.0 grams (87% yield) of the title compound as a white solid melting at 100°-102° C.
Reaction SMILES: [C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH2:11][OH:12])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=[O:12])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(CO)=NN(C(=O)OC(C)(C)C)C1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O

Procedure:
To a stirred solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-(hydroxymethyl)-3-oxo-5H-1,2,4-triazine-2-carboxylate (3.01 g, 7.78 mmol) in CHCl3 (47 mL) was added manganese(IV) oxide (7.96 g, 77.8 mmol) and the obtained mixture was heated under reflux for 20 h. The obtained reaction mixture was filtered over Celite and followed by rinsing with 20% MeOH/CHCl3. Removal of the solvent in vacuo furnished the desired product as a sticky oil which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) 1.43 (s, 9H), 1.52 (s, 9H), 2.48 (s, 3H), 4.26 (dAB, 1H), 4.34 (dAB, 1H), 9.58 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of 5-formyl-2,2'-bithiophene (20 g) in methanol (50 ml) was added sodium borohydride. The reaction mixture was stirred at room temperature and monitored with thin layer chromatography until the reaction completed. After removal of methanol, water was added to dissolve inorganic salts and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated to give product (20.1 g, 99%), melting point 52°-53° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][OH:29])([CH3:27])([CH3:26])[CH3:25]>C1C=CC=CC=1>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][O:13][C:12]1[C:11]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:10][C:7]([CH:8]=[N+:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[O-:29])=[CH:6][C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NO
Reactant: COCCOCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Solvent: c1ccccc1
Product: COCCOCOc1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C

Procedure:
The title compound was prepared in benzene with 3,5-di-tert-butyl-4-(2-methoxy)ethoxymethoxybenzaldehyde and tert-butylhydroxylamine using the procedure described in Example 16. The title compound was isolated (70.1% yield) as a white solid, m.p. 169.6-173.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=O)[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:20][CH2:21][CH3:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:19])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCOC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCOC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
180 mg (0.50 mmol) of [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetic acid (racemate) and 105 mg (0.55 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 265 mg (quant.)
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].C(N(S(F)(F)[F:28])CC)C.O>C(Cl)Cl>[F:28][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 70 %

Procedure:
A solution of 12.1 g (0.04 mol) of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one in 25 ml of anhydrous methylene chloride was added dropwise over a period of 15 min. to a stirred solution of 12.6 ml (0.1 mol) of diethylaminosulfur trifluoride in 300 ml of anhydrous methylene chloride cooled to -70° . The reaction mixture was allowed to warm slowly over a period of 45 min. to 5° and then poured into 500 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to drynes under reduced pressure to give 10.9 g (90% yield) of crude product as a light yellow solid residue. Recrystallization from heptane gave 8.48 g (70% yield) of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 138°-140°; 19F nmr (CCl3D) δ -161.7 ppm (d, J=57 Hz); 1H nmr (CCl3D) δ 3.43 ppm (s, 3H), 5.54 ppm (d, J=57 Hz, 1H), 7.5 ppm (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[NH:32][CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2].[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[N:32]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 11 (560 mg), benzaldehyde (227.4 mg) and acetic acid (128.6 mg) in DMF was stirred under nitrogen at room temperature for 30 minutes. Na(OAc)3BH (568 mg) was added to the solution. The reaction was stirred under nitrogen at room temperature for overnight. The reaction was quenched by the addition of saturated NH4Cl solution (1 mL), followed by the addition of H2O (80 mL) for the attempt of making organic product crashed out of water layer. The solution was cloudy but no solid was formed. The solution was extracted by EtOAc (40 mL×3). The combined organic layer was washed by water (50 mL×2) and brine (50 mL×1), dried by Na2SO4 and concentrated to give crude product (466 mg), which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 3-(4-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester as white solid (290 mg; 44%). 1H NMR (300 MHz, CDCl3) δ 7.59-7.45 (m, 1H), 7.40 - 7.22 (m, 8H), 7.13 (dd, 1H, J=7.0, 7.0 Hz), 6.71 (m, 3H), 5.08 (s, 1H), 4.16 (q, 2H, J=7.0 Hz), 3.98 (m, 1H), 3.70 (m, 2H), 3.35 (m, 2H), 3.25 (m, 1H), 2.84 (m, 3H), 2.66 (m, 6H), 2.47 (m, 3H), 2.11 (m, 2H), 1.93 (m, 1H), 1.70 (m, 1H), 1.27 (t, 3H, J=7.0 Hz), 1.13 (bs, 3H), 1.06 (d, 3H, J=5.5 Hz).
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.[CH3:12][CH2:13][O:14]CC.[O:17]([C@H:25]1[CH2:32][C@H:28]2[O:29][CH2:30][CH2:31][C@@H:27]2[CH2:26]1)[Si](C(C)(C)C)(C)C>C(Cl)Cl>[O:29]1[CH2:30][CH2:31][C@H:27]2[CH2:26][C@H:25]([O:17][C:13](=[O:14])[CH3:12])[CH2:32][C@H:28]12
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CCO[C@@H]2C1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@@H]2CCO[C@H]2C1
Yield: 58 %

Procedure:
To the bicyclic ether (228 mg, 1.065 mmol) and Et3SiH (370 mg, 3.196 mmol) in CH2Cl2 (5 mL) at room temperature, was added BF3.OEt2 (450 mg, 3.196 mmol) following the same reaction conditions as described in the synthesis of compound 3 to obtain compound 5 (140 mg, 58% three steps) as an oil. 1H NMR (CDCl3, 200 MHz): δ 5 (m, 1H), 4.5 (m, 1H), 3.95 (m, 1H), 3.74 (m, 1H), 2.7 (m, 1H), 2.1 (m, 3H), 2 (s, 3H), 1.5-1.9 (m, 3H).
Reaction SMILES: Cl[C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH3:13]>>[CH3:5][C:2]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][O:8][CH3:7])([CH3:6])[C:3]#[CH:4]
Reactant: CCNCCOC
Reactant: C#CC(C)(C)Cl
Product: C#CC(C)(C)N(CC)CCOC

Procedure:
In analogy to example 37.1, 3-Chloro-3-methyl-1-butyne and N-(2-Methoxyethyl)ethylamine were converted to yield (1,1-Dimethyl-prop-2-ynyl)-ethyl-(2-methoxy-ethyl)-amine as colorless oil, MS: 170 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Se](=O)=[O:16]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH:14]=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2C)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cccc(C=O)n1

Procedure:
2.8 g of 6-(2-methylphenyl)-2-methylpyridine was dissolved in 180 ml 1,4-dioxane, 1.4 g of selenium dioxide (Aldrich Gold Label) was added and the mixture refluxed for 36 hours. The solids were removed by filtration. Ether was added and the organic extracts washed five times with 100 ml water. After drying over magnesium sulfate and evaporation, 6-(2-methylphenyl)-2-pyridinecarboxaldehyde was afforded as a pale yellow oil (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH:22]([CH3:24])[CH3:23])=[C:4]([CH:17]([OH:20])[CH2:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].C[N+]1([O-])CCOCC1>>[Cl:1][C:2]1[C:3]([O:21][CH:22]([CH3:23])[CH3:24])=[C:4]([C:17](=[O:20])[CH2:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCC(O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C
Agent: C[N+]1([O-])CCOCC1
Product: CCC(=O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure M, 1-(8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromene-6-yl)-propan-1-ol (Compound 139, 1.05 g, 2.96 mmol) and 4-methylmorpholine N-oxide (520 mg, 4.44 mmol) were reacted to give the title compound as a yellow oil.