Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:5]2[C:6](OC(=O)[NH:10][C:4]=12)=[O:7]>O.CN(C=O)C>[NH2:10][C:4]1[C:3]([Cl:2])=[CH:14][CH:13]=[C:12]([CH3:15])[C:5]=1[C:6]([NH2:1])=[O:7]
Reactant: Cc1ccc(Cl)c2[nH]c(=O)oc(=O)c12
Reactant: N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(N)c1C(N)=O
Temperature: 87.5 °C

Procedure:
A solution of 59 ml (0.78 mol) of 25% strength ammonia solution in 207 ml of water and a mixture of 135.2 g (0.64 mol) of 3-chloro-6-methylisatoic anhydride in 705 ml of DMF were added simultaneously to 150 ml of water via 2 dropping funnels in the course of 30 min with stirring at 85 to 90° C., strong evolution of gas occurring. The mixture was stirred at 90° C. for 2 h and at 22° C. for 10 h. The reaction solution was concentrated in vacuo, and the residue was stirred with methyl tert-butyl ether, filtered off with suction and dried. 67.4 g (57% of theory) of the title compound were obtained as a yellowish powder of m.p. 124-128° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][NH2:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:5][C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][NH:18][C:1](=[O:3])[CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2nc(Cl)cc(CCN)c2c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(Cl)cc(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Acetyl chloride (0.37 g, 4.7 mmol) was added dropwise gradually under ice-cooling to a solution of 2-(2-chloro-6-methoxyquinolin-4-yl)ethylamine (1.0 g, 4.2 mmol) and triethylamine (0.87 g, 8.6 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred at room temperature for 1 hour and poured into water. The organic materials were extracted with a mixed solvent of 5% methanol/ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to obtain the title compound (0.96 g, 80%).
Reaction SMILES: N1C=CN=C1.S(Cl)(Cl)=O.[CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]2[CH:23]=[N:22][C:21]([C:29](O)=[O:30])=[C:20]([CH3:32])[C:19]3=2)[CH2:12][CH:11]=1.[C:33](=[N:37]O)([NH2:36])[CH2:34][CH3:35]>O1CCCC1.CN(C)C=O>[CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]2[CH:23]=[N:22][C:21]([C:29]4[O:30][N:37]=[C:33]([CH2:34][CH3:35])[N:36]=4)=[C:20]([CH3:32])[C:19]3=2)[CH2:12][CH:11]=1
Reactant: CCC(N)=NO
Reactant: Cc1c(C(=O)O)ncc2[nH]c3ccc(C4CC=CCC4)cc3c12
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1noc(-c2ncc3[nH]c4ccc(C5CC=CCC5)cc4c3c2C)n1
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
1.36 g (20 mmol) of imidazole is combined in 15 ml of absolute tetrahydrofuran with 0.36 ml of thionyl chloride in 5 ml of absolute tetrahydrofuran. After 15 minutes of agitation at room temperature, the mixture is suctioned off from the precipitate. The filtrate is added to a solution of 0.33 g (1.08 mmol) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid in 15 ml of absolute dimethylformamide. After agitation for one hour at room temperature, the mixture is combined with 1.15 g (13 mmol) of propionamidoxime, the tetrahydrofuran is distilled off, and the reaction solution is heated for 3 hours under reflux. After the solvent has been removed by distillation, the mixture is distributed in methylene chloride/saturated sodium bicarbonate solution, the organic phase is washed with saturated sodium chloride solution until it is neutral, dried over magnesium sulfate, filtered, and concentrated to dryness. After column chromatography over silica gel with methylene chloride:ethanol=10:1 as the eluent, and recrystallization from ethanol/hexane, the residue yields 194 mg (50% of theory) of 6-(1-cyclohexen-4-yl)-4-methyl-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-β-carboline, mp 247°-248° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].[CH3:11][C:12](O)([C:15]#[N:16])[CH:13]=[CH2:14].P(=O)(O)(O)O.B(F)(F)F>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[OH:4][C:3]1[C:5]([CH3:10])=[C:6]2[C:7](=[CH:8][C:2]=1[CH3:1])[O:9][C:12]([CH3:11])([C:15]#[N:16])[CH2:13][CH2:14]2
Reactant: C=CC(C)(O)C#N
Reactant: Cc1cc(O)cc(C)c1O
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(C)c1O)CCC(C)(C#N)O2
Yield: 79 %

Procedure:
Using the method described in the last paragraph of Example 1, 23.3 g (0.169 mole) of 2,6-dimethylhydroquinone were reacted with 16.6 g (0.169 mole) of methyl vinyl ketone cyanohydrin, stabilized with 1 g of phosphoric acid, in 125 ml of toluene and 17 ml of nitromethane in the presence of 11.5 g (0.169 mole) of BF3. Conventional working up gave 6-hydroxy-2,5,7-trimethyl-2-cyanochromane in the form of colorless crystals, in 79% yield; melting point 135° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=NN=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1>C1COCC1>[C:13]1([C:10]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1=CCCCCCC1
Reactant: c1ccc(-c2nnc(-c3ccccc3)nn2)cc1
Agent: C1=C/CCCCCC/1
Solvent: C1CCOC1
Product: c1ccc(-c2nnc(-c3ccccc3)c3c2CCCCCC3)cc1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A dry round-bottomed flask was charged with 3,6-diphenyl-1,2,4,5-tetrazine (0.030 g, 0.13 mmol) and the flask was evacuated and filled with nitrogen. Anhydrous THF (1.3 mL) and trans-cyclooctene (0.014 g, 0.21 mmol) were added to the reaction mixture. After approximately 20 minutes the purple solution turned yellow, indicating that the reaction had gone to completion. The reaction mixture was concentrated under reduced pressure. The crude yellow residue was chromatographed on silica gel using a gradient (0-50%) of EtOAc in hexanes as the eluent to give 38 mg (95%) of the title compound as a pale yellow solid, mp 163-165° C. The adduction product had aromatized upon workup and chromatography to provide the titled compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.Cl>[CH2:21]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: Oc1ccc(I)cc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(I)cc1

Procedure:
4-Iodophenol (3.03 g, 1.38×10−2 mol), 1-bromododecane (6.65 ml, 2.77×10−2 mol) and K2CO3 (3.81 g, 2.76×10−2 mol) were dissolved in 50 ml of dry DMF and refluxed for 3.5 h under N2. After cooling, the solution was diluted with water, 2M HCl, and extracted with CH2Cl2. The combined organic layers were washed with saturated aq. NaHCO3, water, and dried over Na2SO4. The product was chromatographed on silica gel with 3:1 hexane:CHCl3 as the eluent. Yield=5.274 g (98% based on 3.03 g of 4-iodophenol). 1H NMR (250 MHz, CDCl3): δ 7.53 (d, 2H, J=8.8 Hz, Ph), 6.67 (d, 2H, J=9.0 Hz, Ph), 3.90 (t, 2H, J=6.5 Hz, —OCH2—), 1.76 (quint, 2H, J=6.6 Hz, —OCH2CH2—), 1.13-1.48 (m, 18H, —CH2—), 0.88 (t, 3H, J=6.4 Hz, —CH3). CI MS m/z: 388.125 (M+) (calcd 388.126).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[C:6]([CH:13]3[CH2:15][O:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH4+].[Cl-].[N-:18]=[N+:19]=[N-:20].[Na+]>CO>[N:18]([CH:13]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[N:11]2)[CH2:15][OH:14])=[N+:19]=[N-:20]
Reactant: COc1cnc2cccc(C3CO3)c2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2cccc(C(CO)N=[N+]=[N-])c2n1
Temperature: 65 °C
Yield: 78 %

Procedure:
A mixture of 2-methoxy-8-oxiranyl-quinoxaline (4.7 g, 23 mmol; prepared as in WO 2004/002490), NH4Cl (2.2 g, 1.8 eq.) and NaN3 (3.8 g, 2.5 eq.) in MeOH (60 mL) was heated at 65° C. for 5 h, filtered and concentrated in vacuo. The residue was taken up in EA and washed with sat. NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 1:1) to give the desired intermediate as a beige solid (4.4 g, 77% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5](Cl)(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1>C1C=CC=CC=1>[C:5]([O:4][CH2:3][CH2:2][Br:1])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCCBr
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
2-Bromoethanol (4 g, 32 mmol) was added dropwise to a solution of octanoyl chloride (7.8 g, 48 mmol) and pyridine (5 mL) in benzene (50 mL). The reaction mixture was stirred at room temperature for 24 hours. After evaporation of benzene and pyridine under high vacuum, the residue was redissolved in benzene (100 mL). The solution was washed with water (50 mL), sulfuric acid solution (3×25 mL, 0.5 N), sodium bicarbonate solution (25 mL, 1N), and water (2×75 mL). The benzene layer was dried over Na2SO4. The drying agent was suction filtered, and the benzene was evaporated. The resulting oil was purified by silica gel chromatography using chloroform/methanol (9:1) to give 6.5 g of pure product. Yield 81%; liquid; IR (neat) 2930 and 2850 (aliphatic CH), 1730 (CO ester) cm-1 ; 1H NMR (CDCl3) 0.85-0.95 (t, CH3 (CH2)4), 1.20-1.40 (m, CH3 (CH2)4), 1.55-1.70 (m, CH2 CH2 CO), 2.25-2.40 (t, CH2 CH2 CO), 3.50-3.60 (t, O CH2 CH2 Br), 4.35-4.40 (t, O CH2 CH2 Br).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1([C:16]([CH3:23])([C:20](Cl)=[O:21])[C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH:11]1([C:16]2([CH3:23])[C:20](=[O:21])[C:6]3[C:5](=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH3:1])[C:7]=3[Cl:8])[C:17]2=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C(=O)Cl)(C(=O)Cl)C1CCCC1
Reactant: COc1cccc(Cl)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1C)C(=O)C(C)(C1CCCC1)C2=O

Procedure:
2-Cyclopentyl-2,5-dimethyl-4-chloro-6-methoxy-indan-1,3-dione is prepared following substantially the same procedure described in Example 1, Step A using the following substances:2-Methyl-3-chloroanisole 7 g. (0.045 mole)2-Cyclopentyl-2-methylmalonyl chloride 11.2 g. (0.05 mole)Methylene chloride 400 ml.Aluminum chloride 13.5 g. (0.10 mole)
Reaction SMILES: [N+:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)([O-])=O>[Pd]>[NH2:1][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])N1CCc2ccccc21
Agent: [Pd]
Product: NN1CCc2ccccc21

Procedure:
Substituted indolines are prepared such as by the procedures described in Scheme 21. Substituted amino-indolines 64 are prepared from the nitroindoline 62 and a ketone in the presence of NaHB(OAc)3 to form the 1-substituted indoline 63. The nitroindoline 63 is hydrogenated, such as with H2 in the presence of a catalyst, such as Pd/C, to yield the amino-indoline 64.
Reaction SMILES: O[C:2](O)([C:28]([F:31])([F:30])[F:29])[CH2:3][C:4]([NH:6][C:7]1[C:8]([F:27])=[CH:9][C:10]([Cl:26])=[C:11]([CH:25]=1)[O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:5].O1CCCC1.C(O)(=O)C.[O-:42][C:43]#[N:44].[K+]>O>[Cl:26][C:10]1[CH:9]=[C:8]([F:27])[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([C:28]([F:31])([F:30])[F:29])[NH:44][C:43]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(=O)CC(O)(O)C(F)(F)F)c(F)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
To a solution of 1.0 g of crude methyl [2 -(5-{3,3-dihydroxy-4,4,4-trifluorobutyryl}amino-2-chloro-4-fluorophenoxy)phenoxy]acetate and 3 ml of tetrahydrofuran were added 4 ml of acetic acid and 0.87 g of potassium cyanate, and the mixture was stirred at room temperature for 6 hours and then heated at reflux at 120° C. for 2 hours. After cooling, 30 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of methyl [2-{2-chloro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-4-fluorophenoxy}phenoxy]acetate.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[NH:6][C:7]([NH2:16])=[C:8]2[C:12]([N:13]=1)=[N:11][C:10]([O:14][CH3:15])=[N:9]2)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>CN(C=O)C.ClCCl>[NH2:16][C:7]1[N:6]=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[N:13]=[C:12]2[C:8]=1[N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCBr)CC1
Reactant: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.7 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine (37 mg, 0.166 mmol) in DMF (0.5 ml) was added potassium carbonate (55 mg, 0.398 mmol) followed by a solution of 1,1-dimethylethyl 4-(4-bromobutyl)-1-piperidinecarboxylate (58 mg, 0.181 mmol) in DMF (0.2 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with dichloromethane (5 ml) and washed with water (5 ml). The layers were separated using a hydrophobic frit, the aqueous layer was extracted again with dichloromethane (5 ml) and the combined organic extracts were evaporated. The residue was dissolved in methanol (0.6 ml) and purified by MDAP (Method A). The appropriate fractions were combined and evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a colourless gum (32 mg).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[O:28])[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH:41][N:42]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.C[Si](C)(C)ON>CN(C=O)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH:11]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:34][CH:35]=2)=[O:28])[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21](=[O:23])[NH:42][OH:41])=[O:17])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)C1CCC(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)ON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@H]1CC[C@H](C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)NO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-propionic acid (prepared as described in example 92; 0.2 g, 0.36 mmol) was dissolved in DMF (5 mL) and 1-hydroxybenzotriazole (53 mg, 0.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol) were added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. and N,N-diisopropylethylamine (85 μL, 0.50 mmol) and O-(trimethylsilyl)hydroxylamine (60 μL, 0.50 mmol) were added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL) and was washed with a saturated aqueous solution of sodium chloride (50 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and glacial acetic acid (9:1). This afforded 95 mg (46%) of the title compound as a solid.
Reaction SMILES: Cl.[CH2:2]([N:4]=[C:5]=NCCCN(C)C)C.Cl.CNC.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[C:40]3[C:35](=[N:36][C:37]([CH3:41])=[CH:38][CH:39]=3)[N:34]([CH2:42][CH3:43])[C:33](=[O:44])[C:32]=2[CH2:45][CH2:46][C:47]([OH:49])=O)[CH:28]=[CH:29][CH:30]=1>O.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[C:40]3[C:35](=[N:36][C:37]([CH3:41])=[CH:38][CH:39]=3)[N:34]([CH2:42][CH3:43])[C:33](=[O:44])[C:32]=2[CH2:45][CH2:46][C:47]([N:4]([CH3:5])[CH3:2])=[O:49])[CH:28]=[CH:29][CH:30]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(=O)c(CCC(=O)N(C)C)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
Under ice cooling, 630 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 154 mg of dimethylamine hydrochloride and 0.53 ml of triethylamine were added successively to a 10 ml DMF solution containing 700 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) and then recrystallized from diisopropyl ether to obtain 262 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]-N,N-dimethylpropanamide as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (28 g, 0.178 mol), benzyl bromide (33.53 g, 0.195 mol) and K2CO3 (30.8 g, 0.223 mol) in anhydrous DMF (150 mL) was stirred at room temperature for 12 h. After the reaction was complete, the reaction mixture was poured into a mixture of ether (1000 mL) and water (200 mL). The organic phase was separated, washed with water (3×100 mL), dried (MgSO4) and concentrated to give the title compound of Step A (40.5 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.F[C:13]1[N:18]=[C:17]([S:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([C:29]([NH:31][CH2:32][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:30])=[CH:15][CH:14]=1.CCCCCC.CC(=O)OCC>CN(C=O)C>[C:23]1([CH2:22][CH2:21][CH2:20][S:19][C:17]2[C:16]([C:29]([NH:31][CH2:32][C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[O:30])=[CH:15][CH:14]=[C:13]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[N:18]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(NCc1cccs1)c1ccc(F)nc1SCCCc1ccccc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(NCc1cccs1)c1ccc(N2CCCC2)nc1SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
153 mg of K2CO3 and 71 mg (1.0 mmol) of pyrrolidine were added to a solution of 387 mg (1.0 mmol) of 6-fluoro-2-(3-phenylpropylthio)-N-(thiophen-2-ylmethyl)-pyridine-3-carboxylic acid amide (exemplary compound 225) in DMF (10 ml), and the mixture was stirred for 2 h at RT. Dilution with water and extraction with EA were then carried out. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 308 mg (0.7 mmol, 71%) of 2-(3-phenyl-propylsulfanyl)-6-pyrrolidin-1-yl-N-(thiophen-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 438.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:8][C@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O[C@@H](CC1CCCC1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CC1CCCC1)c1ccccc1
Reaction time: 6 h
Yield: 100 %

Procedure:
A solution of 406 mg (2.13 mmol) of (S)-2-cyclopentyl-1-phenylethanol (from EXAMPLE 20, Step C) in 9 mL of pyridine was treated with 1 mL of acetic anhydride. After stirring for 6 h, the reaction was concentrated. Flash chromatography on silica gel using 7.5% EtOAc in hexane afforded 495 mg (100%) of the title compound: RF: 0.75 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.10-1.21 (m, 2H), 1.44-2.04 (m, 9H), 2.05 (s, 3H), 5.75 (dd, J=8.0, 6.1, 1H), 7.25-7.34 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:18]1([CH:21]=O)[CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH:18]1([CH2:21][N:10]2[CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=3[NH:7][C:8](=[O:12])[CH2:9]2)[CH2:20][CH2:19]1
Reactant: O=CC1CC1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(CC1CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (450 mg, 1.90 mmol) and cyclopropanecarboxaldehyde (2.84 mL, 37.9 mmol) in dichloromethane (50 mL) and methanol (5 mL) was added acetic acid (0.22 mL, 3.8 mmol). After being stirred for two hours at room temperature, sodium triacetoxyborohydride (1.2 g, 5.7 mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was washed with saturated aqueous sodium bicarbonate and brine before being dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (0-5% MeOH-DCM) gave 4-cyclopropylmethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (440 mg, 80%) as a yellow-orange solid; 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.59 (s, 1H), 7.33 (s, 1H), 3.91 (2s, 5H), 3.43 (s, 2H), 2.41 (d, J=6 Hz, 2H), 0.86 (m, 1H), 0.47 (m, 2H), 0.10 (m, 2H); MS (m/e) 292 (M+1); mp 178° C.