Azzindani/Open_Reaction_Data huggingface dataset:
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[OH:11].[CH3:12][NH:13][C:14](Cl)=[O:15]>C(C1C=CC=CC=1)(C)(C)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:14](=[O:15])[NH:13][CH3:12]
Reactant: Oc1ccc2ccccc2c1
Reactant: CNC(=O)Cl
Solvent: CC(C)(C)c1ccccc1
Product: CNC(=O)Oc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
72 parts by weight of β-naphthol are dissolved in 250 parts by weight of t-butylbenzene at 80° C. 46.7 parts by weight of methylcarbamyl chloride are passed into this solution over a period of 10 minutes while nitrogen is simultaneously bubbled through the solution. The reaction is complete after 15 minutes. The hot reaction solution is then cooled to 0° C. 83.5 parts by weight of β-naphthyl-N-methylcarbamate are precipitated, this being equivalent to a yield of 83% of theory. The melting point is 119° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[N:9][CH2:10][Si](C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>O1CCCC1>[CH3:31][O:30][C:26]([CH:27]1[CH2:28][CH2:10][N:9]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]1[C:7]1[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:29]
Reactant: C[Si](C)(C)CN=Cc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)OC
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1CCN(C(=O)c2ccccc2)C1c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of (4-nitro-benzylidene)-trimethylsilanylmethyl-amine (22 g, prepared as described in Chem. Pharm. Bull. 31(11) page 3939, 1893) in tetrahydrofuran (440 ml), at 45° C., was treated dropwise over 1.5 hour with a mixture of benzoyl chloride (10.1 ml) and methyl acrylate (9.3 ml) in tetrahydrofuran (500 ml). After stirring for 2.5 hours at 45° C. the mixture was allowed to cool to 20° C. then evaporated (40° C. and 2.7 kPa). The residue was dissolved in ethyl acetate (800 ml) and the solution was washed with hydrochloric acid (500 ml, 1N), then with aqueous sodium hydroxide solution (500 ml, 1N), then with water (500 ml), then dried over magnesium sulphate and then evaporated (40° C. and 2.7 kPa). The residue was subjected to chromatography on silica (500 g, 0.020-0.045 mm particle size) using a 60 mm internal diameter column and eluting with a mixture of cyclohexane and ethyl acetate (80:20, v/v) at 100 ml/minute affording the title compound (8.33 g) as a yellowish powder. 1H-NMR [500 MHz, (CD3)2SO at 373° K.] δ 2.19 (m, 1H); 2.32 (m, 1H); 3.34 (s, 3H); 3.70 (m, 2H); 4.03 (m, 1H); 5.52 (m, 1H); 7.35 to 7.50 (m, 7H); 8.12 (d, J=8.5 Hz, 2H). MS (EI): 354[M]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[C:16]([CH:18]=[C:19]([O-])[CH3:20])#[N:17].[Na+].[NH2:23]/[C:24](/[CH3:31])=[CH:25]\[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C>CC(O)C>[C:16]([C:18]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:14])=[CH:5][C:4]3=[O:15])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH3:31])[NH:23][C:19]=1[CH3:20])#[N:17]
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Reactant: CC([O-])=CC#N
Reactant: CCOC(=O)/C=C(/C)N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1ccc(F)c2c(=O)cc(C)oc12

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 62.65 mg (0.49 mmol) of ethyl 3-aminocrotonate and 0.04 ml (0.73 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The beige-colored crystals are filtered off with suction and dried at 40° C. in a vacuum drying oven. 120.7 mg (65.1% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.ICCC>CN(C)C=O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH3:3])[CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCN1CCC(O)(c2cccc(F)c2F)C1
Temperature: 80 °C
Yield: 34.5 %

Procedure:
In a sealed tube a mixture of (+)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.40 g, 1.38 mmol), dimethyl formamide (3 mL) and iodopropane (1.35 mL, 13.8 mmol) was heated under microwave irradiation at 80° C. for 45 minutes. The resulting mixture was evaporated, morpholine (2 mL) was added and the mixture was heated under micro-wave irradiation at 130° C. for 30 minutes. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was washed with aqueous LiCl (5%, 50 mL), dried (Na2SO4) and evaporated. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 40:60 to 60:40) gave the title compound (0.115 g). [α]D=+22.8° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 95-98° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 8), 212, (bp), 182 (41), 84 (88), 57 (24).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH:12]([O:14]C(=O)C)[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[OH-].[Li+].O>C1COCC1.CO.O>[Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
Dissolve (-)-acetic acid 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (2.3 mmol, prepared in example 10) in THF/methanol/water (2.7/0.9/0.9 mL). Add lithium hydroxide monohydrate (2.5 mmol) with stirring. After stirring for about 3 hours at room temperature, dilute the reaction with water (10 mL) and extract with tert-butyl methyl ether. Combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, 20% ethyl acetate/hexane) to provide the title compound (452 mg, 92% yield) [α]20D =+21.8°, (c=1.02, chloroform).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>CO>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[O:9][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]2=[O:14]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1ccc(Br)cc1
Agent: [Na]
Solvent: CO
Product: O=c1c2cc(Br)ccc2oc2ncccc12
Temperature: 130 °C
Yield: 2.3 %

Procedure:
Sodium metal (2.30 g, 100 mmol) was added to ice-cooled methanol (75 mL) with stirring under nitrogen. After the sodium had reacted completely, a slurry of 4-bromophenol (8.65 g, 50 mmol) and 2-chloronicotinic acid (7.88 g, 50 mmol) in methanol (50 mL) was added. The resulting light yellow solution was concentrated under vacuum, and the solid residue was taken up in DMF (50 mL) and heated to 130° C. for 18 h. The mixture was cooled, concentrated under vacuum, and the residue was diluted with water (50 mL) and extracted with ether (2×50 mL). The aqueous phase was acidified with 5% sulfuric acid (60 mL) to pH ˜3, and the slurry was stirred for 1 h and the precipitate was isolated by filtration and dried at 50° C. The tan solid (3.48 g), a 3:2 mixture of 2-(4-bromophenoxy)nicotinic acid and 2-chloronicotinic acid, was used directly for the cyclization. The solid (1.0 g) was added in one portion to a solution of phosphorous pentoxide (2.6 g) in methanesulfonic acid (27 g) at 80° C. The brownish solution was heated at 80° C. for 15 h, then cooled and poured onto ice (100 g). The mixture was brought to pH>9 by addition of 50% NaOH (17 mL) and extracted with dichloromethane (2×40 mL). The organic extract was dried (MgSO4) and concentrated to provide the title compound as a white solid (0.32 g, 8% from 4-bromophenol). 1H NMR (300 MHz, CD3OD) δ ppm 7.59 (dd, J=8, 5 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 8.00 (dd, J=9, 3 Hz, 1H), 8.36 (d, J=2 Hz, 1H), 8.73 (dd, J=8, 2 Hz, 1H), 8.78 ppm (dd, J=5, 2 Hz, 1H); MS (DCI/NH3) m/z 276/278 (M+H)+.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].[C:6](Cl)(Cl)=[S:7].[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(Cl)Cl>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:6](=[S:7])[O:4][CH3:1])=[CH:23][CH:22]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=S)Nc1ccc(OCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
20.8 ml of sodium hydrogencarbonate and 0.05 ml of thiophosgen were added to a solution of 50.2 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in Example 3 (b)] in 2 ml of methylene chloride and the resulting mixture was stirred at room temperature for 2 hours. 8 ml of methylene chloride were then added to the reaction mixture and the resulting mixture was washed with water and the organic fraction then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was then dissolved in 3 ml of tetrahydrofuran and 0.01 ml of methanol. 13.2 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting mixture which was then stirred at room temperature for 30 minutes. At the end of this time, 5 mg of sodium methoxide were added to the reaction mixture which was then stirred for 30 minutes. A saturated aqueous sodium chloride solution was then added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 49.7 mg (yield 76%) of the title compound as a solid having a melting point of 160°-162° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CCNS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
Methanesulfonyl chloride (0.082 mL, 1.05 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (300 mg, 1.05 mmol) and N,N-diisopropylethylamine (0.367 mL, 2.11 mmol) in DCM (4 mL) at 20° C. The resulting solution was stirred at 20° C. for 18 hours. The reaction mixture was concentrated and diluted with Et2O (25 mL) and washed with water (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamate (275 mg, 71.9%) as a white solid.
Reaction SMILES: N[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[N:28]1C=CC=CC=1>>[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](=[O:26])(=[O:25])[NH:28][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[CH3:2])=[CH:20][CH:19]=1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(C)(C)C(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Product: CC(=O)c1ccccc1NS(=O)(=O)c1ccc(OC(=O)C(C)(C)C)cc1
Yield: 89 %

Procedure:
2-Aminoacetophenone (1 mmol) and p-pivaloyloxybenzenesulfonyl chloride (1.5 equivalent weights) were added into pyridine (5 mL) to obtain a mixture, followed by subjecting to reaction at room temperature for 4 hours and then removing pyridine under vacuum to obtain a reaction product. The reaction product was purified using a silica gel column (n-hexane/acetone=4:1), thereby obtaining 4-(N-(2-acetylphenyl)sulfamoyl)phenyl pivalate (331 mg, yield 89%).
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][C:17]2[C:18]([CH3:23])=[N:19][NH:20][C:21]=2[CH3:22])[CH:15]=1)[C:11]#[N:12]>CN(C)C=O>[C:3]([N:20]1[C:21]([CH3:22])=[C:17]([O:16][C:14]2[CH:13]=[C:10]([CH:9]=[C:8]([Cl:7])[CH:15]=2)[C:11]#[N:12])[C:18]([CH3:23])=[N:19]1)(=[O:5])[CH3:4]
Reactant: CC(=O)Cl
Reactant: Cc1n[nH]c(C)c1Oc1cc(Cl)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1nc(C)c(Oc2cc(Cl)cc(C#N)c2)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Sodium hydride (60% dispersion in oil, 840 mg, 21.0 mmol) was added to a stirred solution of acetyl chloride (1.50 ml, 21.0 mmol) and the pyrazole of Example 76 (4.80 g, 19.4 mmol) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 15 minutes and then quenched by the addition of water (200 ml). The reaction mixture was extracted with ethyl acetate (3×120 ml). The combined organic phases were washed with water (50 ml) and brine (50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane to provide the title compound (5.00 g) as a white solid, m.p.<60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(Cl)c1ccc(-c2ccc(Br)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(NCCCN1CCOCC1)c1ccc(-c2ccc(Br)cc2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.06 g of 5-(4-bromphenyl)-2-furancarboxylic acid chloride and 2.55 g of N-(3-aminopropyl)morpholine is refluxed 6 hr with 3.0 g of anhydrous potassium carbonate in 50 ml of acetonitrile. The mixture is allowed to stir at room temperature overnight. Solvents are then evaporated and the residue is triturated with ethyl ether followed by evaporation again. This process is repeated several times. A solution of the residue in ethyl ether is allowed to stand overnight whereupon crystals are formed. After three recrystallizations from ethyl acetate, the product, 2.47 g (37.5%), melts at 8°-100° C. The CI and EI mass spec. are consistent with the proposed structure. The latter showed M+ =393.
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])[CH:9]=[CH:10]2)=[N:5]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+]>C1COCC1.C(OCC)(=O)C>[CH:30]1([NH:35][CH2:2][CH2:3][N:4]2[CH:12]=[C:11]3[C:6]([CH:7]=[C:8]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:19][CH:18]=4)=[O:15])[CH:9]=[CH:10]3)=[N:5]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCC1
Reactant: O=CCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2cn(CCNC3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-[2-(2-oxo-ethyl)-2H-indazol-6-yl]-3-(4-phenoxy-phenyl)urea (20 mg, 0.05 mmol) and cyclopentylamine (10 mL, 0.10 mmol) in THF (0.5 mL) was shaken at room temperature for 30 minutes. 1M Sodium cyanoborohydride in THF (104 μL, 0.10 mmol) was added and the solution was shaken at room temperature for 16 hours. The sample was diluted with ethyl acetate, washed with water, concentrated under reduced pressure and purified by RP-HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.6 (m, 6 H), 2.0 (m, 2 H), 3.55 (m, 2 H), 4.35 (m, 2 H), 4.70 (t, 2 H), 6.97 (m, 5 H), 7.12 (m, 1 H), 7.35 (m, 2 H), 7.52 (m, 2 H), 7.65 (d, 1 H), 7.95 (s, 1 H), 8.35 (s, 1 H) and 8.70 (m, 2 H.); MS (ESI) 456 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4](O)=O.[CH3:7][N:8]1[C:12]([CH2:13]Cl)=[N:11][N:10]=[N:9]1.[OH-:15].[Na+]>CC(C)=O>[CH3:7][N:8]1[C:12]([CH2:13][CH2:4][CH2:3][C:2]([OH:15])=[S:1])=[N:11][N:10]=[N:9]1
Reactant: O=C(O)CCS
Reactant: Cn1nnnc1CCl
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1nnnc1CCCC(O)=S
Reaction time: 3 h

Procedure:
3-Mercaptopropionic acid (1.6 g) is dissolved in 1N aqueous sodium hydroxide solution (45 ml) and thereto is added dropwise a solution of 1-methyl-5-chloromethyl-1,2,3,4-tetrazole (15.2 g) in acetone (20 ml) with stirring under ice-cooling. Stirring is continued for 3 hours under ice-cooling. Acetone is distilled off and the residue is acidified with concentrated hydrochloric acid, saturated with sodium chloride and then, extracted with chlorofom. The chloroform solution is dried over magnesium sulfate. After chloroform is distilled off, the residue is subjected to column chromatography (Kieselgel 60, made by Merck) by eluting the column with chloroform-methanol (10:1, V/V) to give 3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionic acid (2.1 g) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[C:18]([Li])(C)(C)C.CI>O1CCCC1.CCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH:15]([CH3:18])[O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: [Li]C(C)(C)C
Reactant: CN(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Solvent: CCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1OC(=O)C=C1N(C)Cc1cnc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
150 mg (0.55 mmol) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one (10) are dissolved in 5 ml of tetrahydrofuran and cooled to −78° C., and 339 μl (0.58 mmol) of a 1.7 M solution of tert.-butyllithium in pentane are added. After 30 min of stirring at −78° C., 36 μl (0.58 mmol) of methyl iodide are added, and the mixture is stirred at −78° C. for a further 30 min and then warmed to room temperature. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (4:1) gives 48 mg (27% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]-5-methylfuran-2(5H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:47][CH3:48])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=2.[ClH:49]>CO.CCOCC>[ClH:49].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:47][CH3:48])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=2
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (33.8 mg, 45.3 μmol) in MeOH (45.3 μl) was added 2 M HCl in Et2O (181 μl). The reaction was stirred at rt for 3 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (29.0 mg, 94%) as a white solid. MS m/z 645/647 (MH)+.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8](=[O:18])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[Cl:17])[C:4]([O:6][CH3:7])=[O:5].[CH:19]1(N)[CH2:21][CH2:20]1>C(#N)C>[CH:19]1([NH:1][CH:2]=[C:3]([C:8](=[O:18])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=2[Cl:17])[C:4]([O:6][CH3:7])=[O:5])[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: COC(=O)C(=CN)C(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: COC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)cc1Cl

Procedure:
2 g of the product from Example 5 and 0.62 g of cyclopropylamine were stirred in 30 ml of dry acetonitrile at room temperature for 30 minutes. The volatile constituents were then stripped off on a rotary evaporator and the evaporation residue was recrystallized from ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[F:16]C1C=CC(F)=CC=1C(Cl)=O>>[F:16][C:12]1[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=1[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: O=C(O)CNC(=O)c1ccc(F)c(F)c1
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: O=C(O)CNC(=O)c1cc(F)ccc1F

Procedure:
2-(2,5-difluorobenzamido)acetic acid was prepared in the same manner as 2-(3,4-difluorobenzamido)acetic acid described above, except that 2,5-difluorobenzoyl chloride was used in place of 3,4-difluorobenzoyl chloride. LCMS (+ESI) m/z 216.2 [M+H]+. 1H-NMR (dmso d6) δ 12.69 (br s, 1H), 8.66 (bdd, 1H), 7.55-7.30 (m, 3H), 7.75 (m, 1H), 3.93 (d, 2H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([CH:17](OS(C)(=O)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH:13]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([S:1][CH:17]([C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:7]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: CCOC(=O)C(OS(C)(=O)=O)C1=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Sc1nc(OC)cc(OC)n1)C1=CCCC1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
10.4 g of 2-mercapto-4,6-dimethoxypyrimidine, 15.0 g of ethyl 2-(1-cyclopentenyl)-2-(methylsulfonyloxy)acetate, 100 ml of N,N-dimethylformamide and 9.2 g of anhydrous potassium carbonate were stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature and then diluted with water. The aqueous mixture was extracted with ethyl ether. The ethyl ether extract was washed with water and dried. Then, ethyl ether was removed by distillation under reduced pressure to obtain an yellow oily substance. The yellow oily substance was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =10/1) to obtain 9.7 g of the desired product.