Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][CH:8]=1.[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH:33][C:13]([C:10]3[CH:9]=[CH:8][C:7]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)=[O:15])=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4ccc(-c5ccccc5)cc4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Add oxalyl chloride (0.20 mL, 2.30 mmol) and 3 drops of DMF to a stirring suspension of Biphenyl-4-carboxylic acid (0.240 g, 1.15 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant biphenyl-4-carbonyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.200 g, 0.768 mmol) and pyridine (0.06 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aqueous) (2×25 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel 130 flash column chromatography (5×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product (0.168 g, 50%). mass spectrum (m/e): 441.3 (M+1). 1H NMR (400 MHz, CD3OD): δ 8.01-7.97 (m, 2H), 7.74-7.70 (m, 3H), 7.67-7.64 (m, 2H), 7.48-7.42 (m, 2H), 7.39-7.31 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 4.12-4.02 (m, 1H), 3.06 (s, 3H), 2.97 (d, J=12.0 Hz, 2H), 2.30 (s, 3H), 2.17 (dt, J=12.4, 2.8 Hz, 2H), 1.91 (dq, J=12.0, 4.0 Hz, 2H), 1.76 (d, J=12.6 Hz, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[S:3].[P:6]([O:11]C)([O:9][CH3:10])[O:7][CH3:8]>C1(C)C=CC=CC=1>[CH3:5][O:4][C:2]([P:6]([O:9][CH3:10])([O:7][CH3:8])=[O:11])=[S:3]
Reactant: COP(OC)OC
Reactant: COC(=S)Cl
Solvent: Cc1ccccc1
Product: COC(=S)P(=O)(OC)OC
Reaction time: 2 h
Yield: 56.5 %

Procedure:
While cooled externally with cold water, 34 g of the crude oil described above was treated with 9 g of chlorine. The temperature should not exceed 30° C. to avoid over-chlorination. The mixture was heated slowly, then fractionated. The fraction boiling at 84-86° C./760 mm was collected, giving 12.7 g of O-methyl chlorothioformate, Y=72%. 1H NMR: δ(ppm) 4.16. [See, Dieter Martin and Wolfgang Mocke, Chemishe Berichte, 98 (7), 2059 (1965).4] A solution of 0.55 g (5 mmol) of O-methyl chlorothioformate in 8 mL of dry toluene was added over 10 min to a solution of 0.62 g (5 mmol) trimethyl phosphite in 15 mL of dry toluene under N2. The mixture was stirred and left for 2 hr at room temperature. The solvent was rotary-evaporated, and the residue distilled in vacuo, giving 0.52 g of a yellow oil, 80-81° C./100μ, Y=56.5%. 1H NMR: δ(ppm) 4.18 (d, 3H, 4JHP=2 Hz, COCH3), 3.87 (d, 6H, 3JHP=11 Hz POCH3); 13C NMR: δ1 (ppm)2.5 (d, 1JCP=223 Hz, PC), 59.1 (d, 2JCP=8 Hz, POCH3), 54.8 (d, 3JCP=6 Hz, COCH 3); 31P NMR {H}: δ(ppm) −1.14 (s); 31 P NMR: δ (ppm) −1.14 (m, 3JPH=11 Hz); HRMS: 185.0031 (MH+, Found); 185.0037 (MH+, Calcd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:12][C:13](=NC#N)NC3C=NC=CC=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])C=CC=CC=1.C(N(CC)CC)C.[Cl:48][C:49]([Cl:53])([Cl:52])[CH2:50][OH:51]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:12][C:13]([O:51][CH2:50][C:49]([Cl:53])([Cl:52])[Cl:48])=[O:31])[CH2:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CN=C(Nc1cccnc1)NC1(c2cccc(Cl)c2)CCC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1(c2cccc(Cl)c2)CCC1)OCC(Cl)(Cl)Cl
Temperature: 71 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
According to the procedure of Ninomiya et al. (Ninomiya, K., Shioiri, T., and S. Yamada, Tetrahedron 30:2151 (1974)), a mixture of the product from Step 2 (1.4 g, 6.65 mmol), diphenylphosphorylazide (2.10 ml, 9.63 mmol) and 1.25 ml (8.95 mmol) of triethyl amine was stirred for 15 minutes and then heated to 71° C. over 60 minutes; 2,2,2-trichloroethanol (0.925 ml, 0.00962 mol) was then added and the mixture was heated at 95° C. for 20 hours and at reflux for 4 hours. The mixture was concentrated and the residue chromatographed over 200 ml of silica gel (230°-400 mesh) by gravity elution with 75% CH2Cl2 /Hexane to give 2.07 g (87.4%) of the titled product.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
40% Methanolic Triton B (0.11 mL, 0.24 mM) was added to a solution of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (70 mg, 0.22 mM) in 20 mL DMF at 0° C. After 15 minutes, methyl bromoacetate (70 mg, 0.44 mM) was added and the resultant mixture stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate, washed with 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was combined with the crude material derived from a similar run utilizing 45 mg (0.14 mM [0.36 mM total]) of 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole. The combined residues were purified by column chromatography on silica gel (elution with ethyl acetate) to afford 76 mg (54%) of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.65 (d, 1H, J=8 Hz), 7.5 (br s, 1H), 7.4-7.15 (m, 9H), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3367, 3200, 1760, 1643, 1579, 1496, 1452, 1427, 1216, 1157, 772, and 716. MS (FD) m/e 388.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].O1CCO[CH2:10]1>[Cl-].[In+3].[Cl-].[Cl-].C(#N)C>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:10][C:3]=2[CH:4]=[CH:5]1
Reactant: C1COCO1
Reactant: OCCc1cccs1
Agent: [Cl-]
Agent: [In+3]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
10.0 g of 2-thiopheneethanol, 11.5 g of 1,3-dioxolane, and 862 mg of indium(III) chloride were added to 780 mL of acetonitrile, and the resulting mixture was refluxed for 10 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. To the residue, 100 mL of water and 150 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 6.6 g (yield of 60%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:25]C)[C:18]([Br:27])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([OH:25])[C:18]([Br:27])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Temperature: 0 °C
Yield: 88.2 %

Procedure:
Aluminium chloride (2.16 g) was added to a stirred solution of methyl 6-(benzenesulfonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 41, 2.15 g) and N,N-dimethylaniline (3.26 g) in DCM (35 mL) and the resultant mixture was stirred for 50 minutes. Ice water and DCM were added and the organic layer was separated, washed with 1M HCl, dried (Na2SO4), filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with DCM to give methyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (1.83 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH3:21][C:22]([CH3:24])=[O:23]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:8][CH2:7][CH2:6][CH2:11][CH2:12][O:23][C:22]2[CH:24]=[CH:4][CH:1]=[CH:2][C:21]=2[CH:15]=[O:18])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1c(OCCCCCOc2ccccc2C=O)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of salicylaldehyde (82 mmoles) in acetone (50 ml) was added dropwise to a refluxing solution of 1,5-dibromopentane (90.2 mmoles), potassium carbonate (90.2 mmoles) and potassium iodide (0.4 g) in acetone (200 ml). The mixture was refluxed for 18 hours, filtered and the filtrate concentrated. The residue was dissolved in ether and washed with cold 10% sodium hydroxide solution, water and brine. The organic layer was dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (4% ethyl acetate/hexane) to give 2-(5-bromopentoxy)benzaldehyde. A mixture of this compound (11.1 mmoles), 4-acetyl-3-hydroxy-2-propyl phenol (11.62 mmoles) and potassium carbonate (5.55 mmoles) in acetone (30 ml) was refluxed for 5 days, stirred at room temperature for 2 days and then refluxed for 24 hours. The suspension was cooled to room temperature, filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate and then washed with ice-cold 5% sodium hydroxide solution, water and brine. The dried solution was concentrated and the product flash chromatographed on silica gel and eluted with ethylacetate/hexane to give the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:10])[O:8][CH:9]=1)=[O:4].[OH-].[Na+]>CCO>[CH3:10][C:7]1[O:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1
Reactant: COC(=O)c1coc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C(=O)O)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the respective 2-acetylamino-3-oxo-propionic acid methyl ester derivative (0.63 mmol, 1.0 eq.) in CHCl3 (0.4 mL) was cooled to 0° C. in an ice/NaCl bath. SOCl2 (0.88 mmol, 1.4 eq.) was added to the stirred solution and the temperature was maintained at 0° C. for 30 minutes. Then the solution was stirred and refluxed for one hour. Another 0.25 eq. of SOCl2 was added and the reaction mixture was refluxed for another hour. The excess SOCl2 was quenched with 1M aq. K2CO3. The aq. layer was extracted twice with ether. The combined organic phases were washed once with water and dried over MgSO4, filtered and concentrated yielding the corresponding 2-methyl-oxazole-4-carboxylic acid methyl ester derivative. The respective 2-methyl-oxazole-4-carboxylic acid methyl ester derivative was dissolved in a mixture of EtOH (0.7 ml) and 2N aq. NaOH (0.7 mL, 2.5 eq.). The mixture was stirred at rt for 2 hours. The reaction mixture was washed once with ether and this organic layer was discarded. The aq. layer was then acidified with conc. HCl and extracted twice with ether. Both organic layers were combined, dried over MgSO4 and concentrated in vacuo to afford the corresponding 2-methyl-oxazole-4-carboxylic acid derivatives.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1)=[O:14]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1cc(Cl)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(Cl)ccn1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
2-Amino-4-chloropyridine (90 mg, 0.70 mmol, 1.1 eq), 3-chlorobenzoic acid (0.1 mg, 0.6 mmol, 1 eq), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (135 mg, 0.704 mmol, 1.10 eq) and 4-dimethylaminopyridine (7.8 mg, 0.064 mmol, 0.10 eq) were dissolved in CH2Cl2 (5 ml) and stirred at rt overnight. Water was added and the layers separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 160 mg (94%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.06 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.6, 1.2 Hz, 1H), 7.67 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.32 (dd, J=5.4, 2.0 Hz, 1H); ES-MS [M+1]+: 267.1.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.Cl.[NH2:23][OH:24].[C:25](=[O:28])([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[C:1]1([CH2:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:25]([NH:23][OH:24])=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NO
Reactant: CCCCCCCC(C(=O)O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(CCCCCCCCc1ccccc1)NO
Yield: 63.1 %

Procedure:
Into a 100 ml, 3 neck flask equipped with thermometer, drying tube, stirrer and dropping funnel is placed phenylnonanoic acid (10 gms, 0.0426 mole) and methylene chloride (20 ml). The resulting stirred mixture is cooled to 5° and thionyl chloride (6.2 gms, 0.052 mole) is added dropwise during 5 minutes, then stirred at room temperature for 18 hours. The methylene chloride and excess thionyl chloride are removed in vacuo to an oil, 10.8 gms (100%). This is diluted with methylene chloride (15 ml) and then added to a stirred mixture of hydroxylamine hydrochloride (3.6 gms, 0.052 mole), anhydrous sodium carbonate (5 gms, 0.052 mole) and methylene chloride (60 ml). During the addition, the temperature of the reaction is maintained between 5°-10° by regulating the addition. After stirring this mixture for 1/2 hour, water (6 ml) is added dropwise during 5 minutes, then the mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with methylene chloride (60 ml) and water (30 ml). The organic layer is separated and washed with water (2×30 ml), brine (2×30 ml), and dried over magnesium sulfate, then filtered and concentrated in vacuo to a solid residue. One recrystallization from methylene chloride (100 ml) gives 6.7 gms (63%) of pure title product, m.p. 75°-7°.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[CH2:10]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:27]1[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:29][CH2:28]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Product: COc1ccccc1N1CCN([C@@H]2Cc3c(OC)ccc(OC)c3C[C@H]2O)CC1
Yield: 50.4 %

Procedure:
A solution of 4.12 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, 4.81 g of 1-(o-methoxyphenyl)piperazine, and 1.53 ml of isopropyl alcohol in 20 ml of xylene is refluxed under nitrogen for 19 hours. The xylene is removed in vacuo and the residue triturated with ether to give 4.01 g of crude material. Two recrystallizations of this material from ethyl acetate yield 2.5 g of the title compound, melting point 182°-183° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=1[OH:29])[CH3:16]>C(O)C.Cl.C(OCC)(=O)C.O>[CH2:7]([O:29][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:21]=1[O:20][CH2:19][CH2:18][O:17][CH2:15][CH3:16])[CH:25]=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: CCOCCOc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOCCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Potassium carbonate (11.3 g, 81.5 mmol) and benzyl chloride (9.5 mL, 82.6 mmol) were added to a solution of 4-(2-ethoxyethoxy)-3-hydroxybenzaldehyde described in Production Example 24-1 (13.2 g, 62.7 mmol) in ethanol (130 mL) under nitrogen atmosphere at room temperature. The liquid mixture was stirred under a thermal condition of 90° C. for 2 hours. The reaction liquid was cooled to 0° C. and then diluted with 2 M hydrochloric acid, ethyl acetate, and water. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The resultant residue was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (13.5 g, 72%).
Reaction SMILES: [O:1]=[S:2]1(=[O:11])[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[C:12]([C:16]1[CH:20]=[C:19]([NH:21][C:22]([C@@H:24]2[CH2:27][CH2:26][NH:25]2)=[O:23])[O:18][N:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl.C(N(CC)C(C)C)(C)C>C1COCC1.ClCCl>[C:12]([C:16]1[CH:20]=[C:19]([NH:21][C:22]([C@@H:24]2[CH2:27][CH2:26][N:25]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:11])(=[O:1])[CH2:3][CH2:4]2)=[O:9])=[O:23])[O:18][N:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2)on1
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2C(=O)N2CCS(=O)(=O)CC2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (51.4 mg; 0.26 mmol) is added to a mixture of (S)-Azetidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (69 mg; 0.265 mmol) and N,N-diisopropylethylamine (0.141 mL; 0.81 mmol) in THF (2 mL). The reaction mixture is stirred at room temperature for 2 hours. After this time, the reaction mixture is diluted with dichloromethane and washed with water. The layers are separated and the aqueous layer is extracted with dichloromethane once. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 385 [M+H+].
Reaction SMILES: ClC1C(F)=C(C=CC=1F)C(Cl)=O.C(OCC)(=O)CC(OCC)=O.[Cl:24][C:25]1[C:26]([F:45])=[C:27]([CH:41]=[CH:42][C:43]=1[F:44])[C:28]([CH:30]([C:36]([O:38][CH2:39][CH3:40])=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29].ClC1C(F)=C(C=CC=1F)C(CC(OCC)=O)=O.C([O-])([O-])OCC.C(OC(=O)C)(=O)C>>[Cl:24][C:25]1[C:26]([F:45])=[C:27]([CH:41]=[CH:42][C:43]=1[F:44])[C:28]([C:30](=[CH:36][O:38][CH2:39][CH3:40])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1ccc(F)c(Cl)c1F
Agent: CCOC([O-])[O-]
Agent: O=C(Cl)c1ccc(F)c(Cl)c1F
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(=O)CC(=O)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F

Procedure:
Reaction of 3-chloro-2,4-difluoro-benzoyl chloride with diethyl malonate gives diethyl (3-chloro-2,4-difluoro-benzoyl)-malonate, and partial hydrolysis and decarboxylation lead to ethyl (3-chloro-2,4-difluoro-benzoyl)-acetate, which is reacted with ethyl orthoformate/acetic anhydride to give ethyl 2-(3-chloro-2,4-difluorobenzoyl)-3-ethoxy-acrylate; further reaction with cyclopropylamine leads to ethyl 2-(3-chloro-2,4-difluoro-benzoyl)-3-cyclopropylaminoacrylate, which is cyclized with potassium carbonateldimethylformamide to give ethyl 8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate; hydrolysis then finally leads to the corresponding carboxylic acid. The reaction sequence described can be represented by the following equation: ##STR4## The quinolonecarboxylic acid obtained in the 6th stage can be converted by reaction with compounds Z--H of the formulae ##STR5## wherein R1 represents hydrogen, straight-chain or branched C1 -C3 -alkyl or cyclopropyl,
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[BH4-].[Na+].[C:25](O)(=O)[CH2:26][CH3:27]>>[CH2:1]([N:3]([CH2:25][CH2:26][CH3:27])[CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CCC(=O)O
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1

Procedure:
Prepared by the method described for Example 59 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.010 moles), propionic acid (20 ml), and sodium borohydride (2.3 g, 0.061 moles). Recrystallization from ethanol gave the product (3.0 g) as the dihydrochloride, 5:1 hydrate, mp 248° C. (dec.).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[NH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=4)=[O:14])[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:35][C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]4)=[O:25])=[CH:19][CH:18]=3)[CH:23]=[C:15]2[C:13]([N:10]2[CH2:9][CH2:8][N:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:5])=[O:6])[CH2:12][CH2:11]2)=[O:14])[CH:39]=[CH:38][N:37]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C4CC4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-cyclopropanesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 33) and 2-chloropyridine-4-boronic acid to afford the desired product as light-brown foam (61%). MS (ISP): 599.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]1=[O:12].CI.[CH3:16][C:17]([OH:19])=[O:18]>CO>[C:17]([O-:19])(=[O:18])[CH3:16].[CH3:11][C:8]1([CH3:10])[CH2:9][N:5]([CH2:4][CH2:3][N+:2]([CH3:16])([CH3:1])[CH3:13])[C:6](=[O:12])[NH:7]1
Reactant: CN(C)CCN1CC(C)(C)NC1=O
Reactant: CC(=O)O
Solvent: CO
Solvent: CI
Product: CC(=O)[O-]
Product: CC1(C)CN(CC[N+](C)(C)C)C(=O)N1
Reaction time: 18 h

Procedure:
To a solution of 1-(2-(dimethylamino)ethyl)-4,4-dimethylimidazolidin-2-one (79.3 mg, 0.428 mmol) in MeOH (5 ml) was added methyl iodide (300 ul, 4.8 mmol). The solution was stirred for 18 h, concentrated in vacuo, dissolved in 2 ml H2O, and Ag2O (300 mg, 1.2 mmol) and AcOH (200 ul, 2 mmol) was added. The suspension was stirred vigorously for 2 h, then filtered through 0.45 um PTFE. The solution was concentrated in vacuo and used without further purification. 1H-NMR (D2O, 400 MHz) δ 1.18 (s, 6H), 1.84 (s, 3H), 3.09 (s, 9H), 3.24 (s, 2H), 3.43 (m, 2H), 3.56 (m, 2H). ESI/APCI (pos) expected for C10H22N3O+: 200.18. Found: 200.