Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CN2CCC1CC2
Product: CC(=O)OC1CN2CCC1CC2
Yield: 95 %

Procedure:
A racemic mixture of (RS) 3-quinuclidinol was dissolved in acetic anhydride and refluxed for three hours to yield a racemic mixture of (RS) 3-acetoxy quinuclidine (b.p. 61°-63° C./0.26 mm Hg; 95% yield). To a boiling solution of 28.28 g of this racemic mixture was added a boiling solution of 25.1 g L-(+)-tartaric acid dissolved in 60 ml of 80% ethanol. The solution was allowed to cool to room temperature, then allowed to stand for several hours, yielding crystals of the (+) hydrogen tartrate salt of 3-acetoxy quinuclidine. This salt was recrystallized three times in 80% ethanol to give 16.77 g of colorless crystals (m.p. 93°-96° C. (froths)). In like manner, the free base obtained from the first mother liquor was then treated with R(-)-tartaric acid and recrystallized to yield 14.5 g of colorless crystals of the (-) hydrogen tartrate salt (m.p. 93°-97° C. (froths)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1.[CH3:22][I:23]>CC(C)=O>[I-:23].[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([CH3:22])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1
Reactant: COc1cnccc1-c1ccc([N+](=O)[O-])c(OC(C)C)c1
Reactant: CI
Solvent: CC(C)=O
Product: COc1c[n+](C)ccc1-c1ccc([N+](=O)[O-])c(OC(C)C)c1
Product: [I-]
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
A mixture of 3.41 g of 3-methoxy-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine and 1.33 ml of methyl iodide in 55 ml of acetone is heated at 50° C. (bath) for 3 h 30. 147 μl of methyl iodide are added and the heating is continued at 50° C. for 50 minutes. The mixture is then concentrated under vacuum, so as to obtain 5.13 g of 3-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in the form of a yellow solid.
Reaction SMILES: Cl[S:2]([C:5]1[C:17]([CH3:18])=[CH:16][C:8]([O:9][CH:10]([CH2:14][CH3:15])C(O)=O)=[CH:7][C:6]=1[CH3:19])(=[O:4])=[O:3].[NH2:20][C@H:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Cl.[C:36]([O-])([OH:38])=[O:37].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O.CCOC(C)=O>[C:27]([O:26][C:24]([NH:23][CH2:22][CH:21]([NH:20][S:2]([C:5]1[C:6]([CH3:19])=[CH:7][C:8]([O:9][CH2:10][CH2:14][CH2:15][C:36]([OH:38])=[O:37])=[CH:16][C:17]=1[CH3:18])(=[O:3])=[O:4])[C:31]([O:33][CH3:34])=[O:32])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=C([O-])O
Reactant: CCC(Oc1cc(C)c(S(=O)(=O)Cl)c(C)c1)C(=O)O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)O)cc1C
Yield: 87 %

Procedure:
A solution of the 4-(chlorosulfonyl)-3,5-dimethylphenoxybutanoic acid, 18 (2.50 g, 8.1 mmol) in dioxane (60.0 g) was added dropwise over a period of about 45 minutes to a mixture of H-Dap(Boc)-OMe.HCl (19) (1.66 g, 6.5 mmol) (Bachem) and NaHCO3 (8.21 g, 97.7 mmol) in water (20.0 g) at rt. Two hours after completion of the addition, the reaction mixture was concentrated in vacuo then water and citric acid (12.50 g, 10.0 eq.) were added. The crude product was extracted with EtOAc and the EtOAc layer was washed once with water. Concentration of the EtOAc layer gave 2.75 g of 20 (87% yield based on 19, 69% based on 18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[Cl:7].S(Cl)(Cl)=O.C1C=CC=CC=1.[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:8]([C:4]1[NH:5][C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=1)=[O:10]
Reactant: O=C(O)c1cc(Cl)c(Cl)[nH]1
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1Cl)c1cc(Cl)c(Cl)[nH]1

Procedure:
4,5-Dichloropyrrole-2-carboxylic acid (10 g., 0.056 mole) was converted to the corresponding acid chloride by reaction with 15 ml. of thionyl chloride, and the acid chloride dissolved in 25 ml. of benzene was reacted with 9.2 g. (0.057 mole) of 2,4-dichloroaniline in 50 ml. of pyridine using the procedure described above in Example 3. The product was recrystallized from an ethyl acetate/ethanol mixture to give 10.0 of 2',4,4',5-tetrachloropyrrole-2-carboxanilide, m.p. 262°-264° C.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C(Cl)CCl.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25](O)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:25](=[O:26])[CH2:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[Cl:15])[CH3:2]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ethanol (8.72 mL, 150 mmol), DMAP (304 mg, 2 mmol), EDC (9.56 g, 50 mmol), and triethylamine (6.91 mL, 50 mmol) were added under cooling (ice) to a solution of (2-chloro-4-methoxy-phenyl)-acetic acid (10.00 g, 50 mmol, [CAS Reg. No. 91367-09-8]) in CH2Cl2 (200 mL). The reaction mixture was stirred at r.t. overnight, then diluted (CH2Cl2), and washed (1N aqueous HCl). The organic layer was dried (Na2SO4), and the solvent was evaporated. Purification of the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-70:30) gave the title compound (7.27 g, 64%).1H NMR (300 MHz, CDCl3) □ 7.18 (1H, d), 6.94 (1H, d), 6.79 (1H, dd), 4.17 (2H, q), 3.79 (3H, s), 3.69 (2H, s), 1.26 (3H, t).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.[C:24]([O:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])[CH3:25].C(OCC(Cl)=O)C1C=CC=CC=1>>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16]([C:29](=[O:30])[CH2:28][O:27][C:24](=[O:26])[CH3:25])[CH2:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C(Cl)COCc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)cc2)C(=O)O1

Procedure:
Following the general procedure of EXAMPLE 18, and making non-critical variations but substituting (S)-(-)-N-[[2-oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 58) for (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide and acetoxyacetyl chloride for benzyloxyacetyl chloride, the title compound is obtained, HRMS calcd for C21H25N3O6: 415.1743. Found: 415.1752.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.ClCCl.COCCN(S(F)(F)[F:31])CCOC.C(=O)(O)[O-].[Na+]>O>[F:31][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(F)CC1
Temperature: 25 °C

Procedure:
A 1-L, round bottom flask was charged with 12.64 g (51.4 mmol) of benzyl 4-oxo-1-piperidinecarboxylate and 300 mL of dichloromethane. To the stirring solution at −78° C. was added 19 mL (102.8 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 1 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise with caution to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate solution, twice with 10% aqueous hydrochloric acid solution and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography on a Biotage® system (gradient, hexane to 65% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:13].CO[C:16](=N)[C:17]([Cl:20])([Cl:19])[Cl:18]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[N:13]=[C:16]([C:17]([Cl:20])([Cl:19])[Cl:18])[NH:12][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COCCOc1cccc(N)c1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COCCOc1cccc2[nH]c(C(Cl)(Cl)Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.33 g (7.30 mmol) 3-(2-Methoxy-ethoxy)-benzene-1,2-diamine were dissolved in 35 mL acetic acid. 1.25 mL (10.22 mmol) 2,2,2-trichloro-acetimidic acid methyl ester were added and the resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and the residue was co-distilled twice with 20 mL toluene to give crude 4-(2-Methoxy-ethoxy)-2-trichloromethyl-1H-benzoimidazole as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH2:13]([C:17]1[C:25]([Cl:26])=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1)[CH2:14][CH2:15][CH3:16]>>[ClH:26].[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([Cl:26])[C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][C:19]=2[O:27][CH3:28])[CH2:7]1
Reactant: CCCCc1cc(OC)c(C(=O)O)cc1Cl
Reactant: CN1CCc2c(N)cccc2C1
Product: CCCCc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1Cl
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-n-butyl-2-methoxy-5-chlorobenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[N:45]1([CH2:50][CH2:51][NH2:52])[CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:52][CH2:51][CH2:50][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:43])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: NCCN1CCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN4CCCC4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-tetrahydro-1H-1-pyrrolyl-1-ethanamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound 42 mg, yield 30%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16]>>[O:16]=[C:7]1[CH2:6][C:15]2[CH:14]=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: O=C1CCc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Product: O=C1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To chlorosulfonic acid (4.5 mL, 68 mmol), cooled to 0° C. in an ice-bath, was added 2-tetralone (1.8 mL, 14 mmol) dropwise over 45 min. After stirring at 0° C. for 2 hours, the mixture was poured slowly into crushed ice (˜50 mL). After stirring for 1 hour, the mixture was extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with H2O (2×20 mL) and saturated brine (20 mL), dried (Na2SO4), and concentrated in vacuo to give 0.67 g (20%) of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl chloride as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.91 (d, 1H, J=8.1 Hz), 7.82 (s, 1H), 7.50 (d, 1H, J=8.1 Hz), 3.70 (s, 2H), 3.20 (t, 2H, J=6.6 Hz), 2.61 (t, 2H, J=6.6 Hz). The crude product was sufficiently pure and it was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:8][C:7]=2[CH:29]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.065 g, 0.15 mmol) and triethylamine (0.044 ml, 0.32 mmol) in dichloromethane (5 ml) was added methanesulfonyl chloride (0.013 ml, 0.17 mmol) at room temperature. After stirring for 20 h the reaction mixture was transferred directly onto a silica gel chromatography column. Elution with n-heptane/ethyl acetate gave the title compound (0.051 g, 72%) as white solid. MS m/e: 473 (M+H+).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=2[CH:3]=1.C([Li])CCC.[C:36](=[O:38])=[O:37].Cl>O1CCCC1>[CH2:23]([C:5]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]2[CH:3]=[C:2]([C:36]([OH:38])=[O:37])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C=O
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Into a flask fitted with a nitrogen inlet and rubber septum were introduced 2-bromo-9,9-dioctylfluorene (34.18 g, 72.8 mmole) and dry tetrahydrofuran (300 mL). The solution was cooled to −60° C. and n-butyl lithium (29.1 mL, 2.5M in hexanes, 72.8 mmole) added via a syringe. The reaction mixture was observed to turn red. After stirring for 1 hour at −60° C., the reaction mixture was poured onto powdered dry-ice and left to stand overnight. The mixture was acidified with 1M HCl and extracted with chloroform. The chloroform extract was washed with water, dried over magnesium sulfate and concentrated to give the required acid as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16]1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[CH2:25]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:15]([NH2:14])[CH2:16]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (3mL) was added to a solution of (1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (481 mg, 1.42 mmol) in dichloromethane (6mL), stirred for 30 minutes at ambient temperature, and concentrated. A solution of the resulting oil in methanol (10 mL) was treated with potassium carbonate (393 mg, 2.84 mmol), stirred for an hour at room temperature, and concentrated to afford the title compound as yellow residue. MS (DCI/NH3) m/z: 239.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)(=O)C>N1C=CC=CC=1.O>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:33]4[CH2:32][CH2:31][N:30]([C:27]5[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=5)[CH2:35][CH2:34]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Yield: 67.1 %

Procedure:
1-Ethyl-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 1.75 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.6 g of 4-(4-fluorophenyl)piperazine in 18 cm3 of pyridine. The solid obtained was taken up in 10 cm3 of water and 1.9 cm3 of 10% acetic acid were added. The suspension was brought to approximately 100° C. The solidified product was filtered off and washed 2 times with 10 cm3 of water and 2 times with 10 cm3 of warm ethanol. After recrystallizing twice from 25 cm3 of dimethylformamide on each occasion, 1.7 g of 1-ethyl-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a pinkish-beige solid melting at about 311-312° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C(Cl)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cccnc2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
3.2 g (14.3 mmol) of 3-cyclopentyloxy-4-methoxy-phenylamine (Garcia et al., JOC, 2005, 70, p 1050) were dissolved in 120 ml of DCM. The solution was cooled to 0° C. and 15 ml (107.6 mmol, 7.5 eq.) triethylamine and 3.7 g (26.1 mmol; 1.8 eq) nicotinoyl chloride in 50 ml DCM were added to the reaction mixture. The reaction mixture was stirred for 2 h and then a solution of 1.3 g NaOH in 50 ml water was added to the mixture. The organic phase was separated and washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-hexane 1:1) to afford 4 g (85%) of the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C(#N)C.C(N(CC)CC)C>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:5][O:6][C:7]([C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1)=[O:8]
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)OC(F)(F)O2
Temperature: 75 °C
Reaction time: 15 h
Yield: 212.8 %

Procedure:
A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75° C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3] dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH3:20])=[O:7].CO>C1COCC1>[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][C:18]=1[CH3:19])=[O:7]
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1cc(N2CCCC(CO)C2)ccc1F
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 4-[[2-fluoro-5-[3-(hydroxymethyl)-1-piperidyl]benzoyl]amino]-3,5-dimethyl-benzoate (0.18 g, 0.43 mmol) in THF:MeOH (3 ml:1 ml). After 16 h at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl and extracted with CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a white solid (0.12 g, 69%). Mass spectrum (m/z): 401.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14](O)=[O:15])([O-:3])=[O:2].O.CCCCCC>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
22.6 g (100 mmol) 2,4-dinitrophenylacetic acid are dissolved in 150 ml tetrahydrofuran and added dropwise in a the course of 2 hours to 300 ml (300 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydrofuran. After 3 hours at 25° C., 200 ml water are carefully added. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 400 g silica gel using toluene:ethyl acetate 1:1 as eluant and crystallization form ethylacetate:hexane mixture to yield 20.7 g (98%) of 2-(2,4-dinitrophenyl)ethanol as yellowish crystals.