Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:38])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:31])[C:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=[O:4].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[C:13]([C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][CH3:23])=[N:17][CH:16]=2)=[C:12]2[C:7](=[CH:8][CH:9]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:10](=[O:31])[NH:11]2)[C:3]([OH:4])=[C:5]1[C:6]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCCC(=O)O
Reactant: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(C2=C3NC(=O)C(c4ccccc4)C=C3C(O)=C(C(=O)NCCC(=O)O)N2Cc2ccccc2)cn1
Temperature: 25 °C
Yield: 121.7 %

Procedure:
A mixture of 1-benzyl-8-(2-ethoxy-pyrimidin-5-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.11 mmol), β-alanine (818 mg, 9.13 mmol) and NaOMe solution (13.7 mL, 6.85 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 38 mg of the title compound as a light yellow solid. MS: (+) m/z 566.38 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8]O.[ClH:11].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[ClH:14].[Cl:11][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][Cl:14]
Reactant: CN(CCCO)CCCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(CCCCl)CCCCl
Reaction time: 15 h

Procedure:
A solution of about 60 grams of N,N-bis(3-hydroxypropyl)methylamine in 110 ml of chloroform is saturated, with cooling and stirring, with anhydrous hydrogen chloride gas. To the resulting two-phase liquid mixture is added, over a period of about 30 minutes at a temperature of 0-5° C., approximately 66 ml of thionyl chloride. The homogeneous solution thus obtained is allowed to stand at room temperature for a period of about 15 hours, the solution is then heated at reflux temperature for an additional two-hour period, and the chloroform is evaporated in vacuo from the light brown-colored reaction solution. The residual material is washed with ethanol, and is then crystallized from a mixture of 200 ml ethanol: 800 ml ether. The white crystalline product thus obtained is recovered by filtration, washed with three portions of ether, then with hexane, and dried in vacuo at 25° C. to give about 80 grams of N,N-bis(3-chloropropyl) methylamine hydrochloride; m.p. 86-88° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]3)[CH:10]=[CH:11][C:12]=2[Cl:16])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C[C@@H]1CN(c2ccc(Cl)c(N)c2)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2ccc(Cl)c(NS(=O)(=O)c3ccc(Br)cc3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-chloroaniline (D34) (108 mg, 0.45 mmol) in pyridine:dichloromethane (1:1, 4 ml) was treated with 4-bromobenzenesulfonyl chloride (138 mg, 0.54 mmol). The solution was stirred at room temperature for 2 hours, quenched with methanol and concentrated in vacuo. The residue was applied to a SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (FlashMaster) (dichloromethane to 5% methanol:dichloromethane) to afford some pure product. The impure fractions were purified further by MDAP, and combined with the above pure product to afford the title product (D35). MS (ES+) m/e 458/460/462 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:20][NH2:21]>>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[NH:20][NH2:21])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Nc1cc(F)cc(F)c1)Oc1ccccc1
Reactant: NN
Solvent: O
Product: NNC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solid 100 mg of O-phenyl 3,5-difluorophenylcarbamate 0.7 mL of hydrazine monohydrate was added. After stirring for 3 h at room temperature a white solid is collected by filtration, washed with water and ether. Removal of traces of the solvents in vacuo gives 4-(3,5-difluorophenyl)-semicarbazide: m.p. 177°-179° C.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12]CC)=O)=[CH:5][CH:4]=1.[NH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:10](=[O:12])[NH:23][C:21](=[O:22])[NH:20][C:15]2=[O:17])=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(C2C(=O)NC(=O)NC2=O)cc1

Procedure:
To a solution of sodium (184 mg) in 12 ml of ethanol are added 0.95 ml of diethyl 2-(4-methylphenyl)malonate and 360 mg of urea, then the mixture is refluxed for 3 hours. A white solid separates, which is filtered and redissolved in 4 ml of water. The solution is acidified to pH=1-2 by adding 6 N hydrochloric acid, A white solid separates, which is collected by filtration, washed with 15 ml of water and dried under vacuum. 619 mg of the product are obtained. m.p. 271° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([NH:8][NH2:9])=[O:7])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:7])[NH:8][NH:9][C:11](=[O:14])[CH2:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)CC(=O)NN
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)NNC(=O)CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of hydrazinocarbonylacetic acid ethyl ester (1.0 g, 6.84 mmol) and diisopropypethylamine (1.77 g, 13.69 mmol) in THF (7 mL) is added a solution of propionyl chloride (633 mg, 6.84 mmol) in THF (2 mL) dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to furnish 3-oxo-3-(N′-propionylhydrazino)-propionic acid ethyl ester. 1H-NMR (400 MHz, CDCl3); δ ppm 1.21 (t, 3H), 1.30 (t, 3H), 2.31 (q, 2H), 3.43 (s, 2H), 4.23 (q, 2H), 8.27 (s, 1H), 9.63 (s, 1H).
Reaction SMILES: [I-].[Na+].Cl[CH2:4][C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.[CH2:15]([O:22][C:23]([NH:25][CH:26]([C:32]([O:34]CC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+]>C(O)C>[CH2:15]([O:22][C:23]([NH:25][C:26]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:4][C:5](=[O:6])[NH:7][C:32]1=[O:34])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: NC(=O)CCl
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To 123 kg of ethanol, 25.0 kg (167 mol) of sodium iodide and 14.2 kg (152 mol) of α-chloroacetamide were added and the resultant mixture was heated to 77° C. and was stirred for 3 hours. To the resultant suspension, 58.2 kg (130 mol) of 69% toluene solution of diethyl 2-benzyloxycarbonylaminomalonate was added, followed by cooling the resultant mixture to 0° C. Thereto, 89.1 kg (262 mol) of 20% ethanol solution of sodium ethoxide was dropped for 3 hours while maintaining the temperature at 0° C. After the reaction mixture was stirred for 3 hours at 0° C., the reaction was quenched by adding 7.9 kg of acetic acid and 15.1 kg of 85% phosphoric acid to the reaction mixture and the solvent was distilled off under reduced pressure. To the reaction mixture, 200 kg of toluene and 80 kg of water were added and the phase separation of the reaction mixture was performed. After the organic phase was washed with water 3 times, it was quantitatively analyzed and the yield of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide was found to be 87.5%. This solution was concentrated and then was recrystallized with toluene and ethanol to thereby obtaining 30 kg (yield: 72%) of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide as a white crystal.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:12]1([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:15][CH:14]([OH:16])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(O)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-hydroxy-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.69 g, 3.05 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give [1,3′]Biazetidinyl-3-ol as a colourless oil (0.225 g, 58%). LCMS (Method A): RT=0.29 min, [M+H]+ 288.9
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH3:26][N:27]([CH3:47])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:26])[CH3:47])=[N:33][CH:34]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN(C)CCCOc1ccc(-c2cc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Yield: 33 %

Procedure:
Similarly, reaction of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole and N,N-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxy}-1-propanamine, as in Example 47, gave N-[3-({5-[2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]-2-Pyridinyl}oxy)propyl]-N,N-dimethylamine in 33% yield: mp (CH2Cl2/hexanes) 140-141° C.; 1H NMR (DMSO-d6) δ 9.07 (d, J=2.2 Hz, 1H), 8.53 (dd, J=8.8, 2.5 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.80 (t, JHF=52.8 Hz, 1H), 7.52 (dt, J=7.8, 1.0 Hz, 1H), 7.50 (dd J=8.1, 1.0 Hz, 1H), 7.42 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 4.39 (t, J=6.6 Hz, 2H), 3.85-3.84 (m, 4H), 3.78-3.76 (m, 4H), 2.39 (t, J=7.1 Hz, 2H), 2.17 (s, 6H), 1.89 (quintet, 2H); Anal. Calcd. for C26H29F2N7O: C, 61.3; H, 5.7; N, 19.2. Found: C, 61.0; H, 5.5; N, 19.1%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:46])[N:14](COC)[C:13](=[O:18])[C:12]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:25]=[C:26]([CH:37]=[C:38]([O:40][C@H:41]4[CH2:45][CH2:44][O:43][CH2:42]4)[CH:39]=3)[C:27]([NH:29][C:30]3[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][N:31]=3)=[O:28])=[CH:22][C:11]=2[O:10]1>C(Cl)Cl>[CH3:8][C:9]1([CH3:46])[NH:14][C:13](=[O:18])[C:12]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:25]=[C:26]([CH:37]=[C:38]([O:40][C@H:41]4[CH2:45][CH2:44][O:43][CH2:42]4)[CH:39]=3)[C:27]([NH:29][C:30]3[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][N:31]=3)=[O:28])=[CH:22][C:11]=2[O:10]1
Reactant: COCN1C(=O)c2ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4cnc(C)cn4)c3)cc2OC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3)OC(C)(C)NC4=O)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.5 %

Procedure:
Trifluoroacetic acid (1 mL) was added to 3-({2,2-dimethyl-3-[(methyloxy)methyl]-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl}oxy)-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (54 mg, 0.1 mmol) and stirred at RT for 48 hours. DCM was added and the solvent removed in vacuo. Ethyl acetate (50 mL) was added and the mixture washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 0-2.5% methanol in ethyl acetate, to give the desired compound as a white foam (14 mg).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:27])[NH:25][NH2:26]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:27])[NH:25][N:26]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: Cc1cccc(Cl)c1NC(=O)NN
Agent: Cl
Product: Cc1cccc(Cl)c1NC(=O)NN=c1c(=O)c2ccccc2c1=O

Procedure:
ninhydrin, 4-(2-chloro-6-methylphenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:19])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:25][CH2:26]O>>[CH2:25]([O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[Cl:19])[CH3:26]
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-benzyloxy-2-chloro-phenyl)-acetic acid (1.5 g, 5.4 mmol) in EtOH (30 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was worked up to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([N:9]1[C:10]2[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (7.7 g, 191.7 mmol) was added portionwise to a 0° C. solution of 4-methoxyindole (21.7 g, 147 mmol) in 750 mL of anhydrous DMF. After 15 min, the slurry was treated with benzyl bromide (17.5 mL, 147 mmol). The reaction mixture was allowed to warm to ambient temperature and stir overnight. The reaction mixture was poured into 1 L of H2O. The layers were separated, and the aqueous phase was extracted with EtOAc (2×200 mL). The combined organic layers were washed with H2O (4×500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2; hexanes) to give 32.9 g (138.6 mmol; 94%) of the title compound as a white solid. Electrospray MS 238 (M+1);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:28][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]2[CH3:21])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1CCCCC1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC2CCCCC2C)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 20.0 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 100 ml of abs. DMF was added 27.8 g of potassium carbonate, followed by 12.5 g of 2-methylcyclohexylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 4 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 29.4 g (100%) of 4-(2-Methyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester. C15H20N2O4 (292.34), LCMS (method 7—1—1): Rt=1.85 min, m/z=293.25 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:10][OH:11])[O:7][N:6]=1)=[O:4].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].N1C=CC=CC=1>>[C:13](=[O:14])([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)[O:11][CH2:10][C:8]1[O:7][N:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:9]=1
Reactant: CNC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1

Procedure:
The process is performed according to the procedure described in Example 4 (step 4.2.). Starting with 2.00 g (12.81 mmol) of 3-methylcarbamoylisoxazol-5-ylmethanol, 2.58 g (12.81 mmol) of 4-nitrophenyl chloroformate, 1.52 g (19.21 mmol) of pyridine and 0.157 g (1.28 mmol) of N,N-dimethylaminopyridine, 2.6 g (63%) of pure product are obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7](O)[CH:8]=2)[O:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][C:2]1([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([C:20](=[O:22])[CH3:21])[CH:8]=2)[O:3]1
Reactant: Cc1c(O)cc2c(c1C)OC(C)(CCC(=O)O)CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)c1cc2c(c(C)c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C

Procedure:
Racemic 2,7,8-Trimethyl-2-(β-carboxyethyl)-6-hydroxy chroman (500 mg) (see Example 11) was dissolved in pyridine (20 mL) at room temperature, and acetic anhydride (10 mL) was added. The solution was maintained at room temperature for 5 hours, solvent was removed under vacuum, methanol (4×10 mL) was added and then removed under reduced pressure. The residual oil was dissolved in ethyl acetate (150 mL) and the organic phase was washed with water (50 mL), aqueous HCl (1 N, 50 mL) and water (50 mL), then dried over sodium sulfate. Solvent was then removed, and the residual oily material was purified on a silica gel column with hexane/ethyl acetate (1:1). The desired product crystallized from acetone/hexane, m.p. 105-107° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.CC(C)=O.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c2ncccc12
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c2ncccc12
Reaction time: 4 h
Yield: 55.1 %

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol) in acetone (15 ml) anhydrous potassium carbonate (300 mg, 2.2 mmol) and benzylbromide (0.25 ml, 360 mg, 2.1 mmol) were added at 50° C. and the stirring was-continued for other 4 h at this temperature. The solvent was removed under reduced pressure, the residue taken up with dichloromethane, the organic layer washed several times with water, dried (sodium sulfate) and evaporated under vacuum. The residue was chromatographed on silica gel using as eluant ethylacetate/cyclohexane (2:3) to give 290 mg (55% yield) of 8-benzyloxyquinoline-5-carbaldehyde. The above obtained compound (290 mg, 1.1 mmol) was dissolved in ethanol (10 ml), then 2-oxindole (170 mg, 1.28 mmol) and piperidine (0.15 ml) were added and the, mixture maintained for 4 h at about 60° C. After cooling the precipitate was filtered, washed with cold ethanol and dried to give 300 mg (72% yield) of raw 3-(8-benzyloxyquinol-5-ylmethylen)-2-oxindole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:42])[CH2:9][CH2:10][N:11]([CH2:13][CH:14]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([OH:36])=O)[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[N:15]1[CH3:41])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][O:44][CH:45]([O:53][CH3:54])[CH2:46][N:47]([CH3:52])[S:48]([NH2:51])(=[O:50])=[O:49].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:28]1([C:27]2[C:26]3[CH:25]=[CH:24][C:23]([C:34]([NH:51][S:48]([N:47]([CH2:46][CH:45]([O:44][CH3:43])[O:53][CH3:54])[CH3:52])(=[O:50])=[O:49])=[O:36])=[CH:22][C:21]=3[N:19]3[C:18]=2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[N:15]([CH3:41])[CH:14]([CH2:13][N:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH3:42])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:20]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)CC1Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2N1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)C(=O)OC(C)(C)C)N(C)c1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, N-(2,2-dimethoxyethyl)-N-methylsulfamide (2 eq, Example 1, Step 1) and DMAP (5 eq) were dissolved in DCM (0.06M) and EDC (3 eq) was added. The mixture was warmed to 40° C. Within 5 min the clear yellow solution turned dark brown. The mixture was stirred overnight. After dilution with DCM the solution was extracted with 1N HCl, sat. aq. NaHCO3 and brine. After drying the organic phase over Na2SO4 the solution was discoloured with activated charcoal. All volatiles were evaporated in vacuo leaving tert-butyl {2-[({13-cyclohexyl-10-[({[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-amino)carbonyl]-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-6-yl}methyl)(methyl)amino]ethyl}methylcarbamate as a glassy brownish solid (MS (ES+) m/z 755 (m+H)+). The material was dissolved in DCM (0.03M) and water was added. To the biphasic system TFA was added and then the vigorously stirred mixture was warmed to 40° C. After 2 h the acetal was completely cleaved, while some N-Boc-protected material was still around. More TFA was added until a monophasic system was obtained. Heating was continued for 3 h. Then all volatiles were evaporated in vacuo and the residual material was coevaporated three times with toluene. The residual sticky material was digested with Et2O leaving a dark red powder. This material was used without further purification in the next reaction. (ES+) m/z 609 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1.O>C1COCC1.O>[N:11]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C1CNC1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2[nH]c(N3CCC3)nc2c1
Temperature: 180 °C
Yield: 17.6 %

Procedure:
[step 1] Commercially available 2-chloro-1H-benzo[d]imidazole (200 mg, 1.31 mmol) was dissolved in THF (1.9 mL), azetidine (0.27 mL, 3.93 mmol) and water (0.27 mL, 0.015 mmol) were added, and the mixture was stirred with heating in an Emrys Optimizer microwave synthesizer at 180° C. for 3 hr. Water was added to the mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-90/10 v/v) to give 2-(azetidin-1-yl)-1H-benzo[d]imidazole (40 mg, 18%).