Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[C:23](C#N)=[C:22]([CH2:26][CH3:27])[NH:21][N:20]=1>C(O)(=O)C>[CH2:26]([C:22]1[C:23]([C:19]#[N:18])=[C:17]2[N:2]=[CH:3][CH:4]=[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)[N:20]2[N:21]=1)[CH3:27]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCc1[nH]nc(N)c1C#N
Solvent: CC(=O)O
Product: CCc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 7.29 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 4.08 g. of 3-amino-5-ethylpyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed for 15 hours and then evaporated to a residue. This residue is treated as described in Example 1, giving the desired product, m.p. 144°-146° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[CH2:11]=[O:12]>CS(C)=O.[OH-].[K+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12])([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1CCO
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 55.8 %

Procedure:
KOH (21 mg, 0.37 mmol) was added to a mixture of o-nitrotoluene (9.2 g, 67 mmol) and paraformaldehyde (0.8 g, 25 mmol) in DMSO (10 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) which was then stirred for 2.5 h at 95° C. The solvent was removed and the residue purified by column chromatography (SiO2, 20×3 cm, solvent: toluene 750 ml, toluene/EtOAc 10:1 500 ml, 7:1 500 ml, 5:1 500 ml). 2-(2-nitrophenyl)ethanol (2.33 g, 21%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1>C(O)C.[Pd]>[CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]([CH3:9])[O:3]1
Reactant: Cc1cc(=O)cc(C)o1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CC(=O)C[C@H](C)O1
Reaction time: 8 h

Procedure:
A solution of 2,6-dimethyl-4-pyrone (5.0 g, 40.3 mmol) in ethanol was charged with Pd/C (0.86 g, 0.40 mmol). The mixture was subjected to pressurized H2 conditions using a parr hydrogenator (50 psi) and the mixture was shaken overnight. Afterwards, the mixture was filtered through a pad of celite, and the filtrate was concentrated. The crude material was purified by column chromatography using 5% to 60% EtOAc-hexanes eluent. The desired fractions were combined and concentrated to give cis-2,6-dimethyldihydro-2H-pyran-4(3H)-one as a colorless oil. Step 2: A solution of cis-2,6-dimethyldihydro-2H-pyran-4(3H)-one (2.05 g, 16.0 mmol) and hydroxylamine chloride (0.73 mL, 17.6 mmol) in methanol was heated to 60° C. for 2 h. After the mixture was cooled to RT, a spatula full of Raney nickel (0.19 g, 3.20 mmol) was added to the reaction mixture. The reaction was subjected to H2 atmosphere using a balloon. The mixture was stirred overnight at 50° C. The reaction mixture was filtered through a pad of celite. The filtrate was acidified with HCl (4.0 mL, 15.99 mmol)-4N in dioxane, and the resulting solution was concentrated. The resulting solid was washed with ether and filtered to give cis-2,6-dimethyltetrahydro-2H-pyran-4-amine hydrochloride as a white solid. The titled compound was prepared by following the procedure described in Example 10, Step 2 to give (2R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpropanamide. MS (ESI, pos. ion) m/z: 433 (M+1).
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>ClCCl.CO>[C:1]1([N:7]([CH2:31][CH2:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:27][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOC(=O)NC(=N)c1ccc(CCc2nc3cc(C(=O)N(CCc4nnn[nH]4)c4ccccc4)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl]-amide and n-hexyl chloroformate. Yield: % of theory, C34H39N9O3 (621.7) Rf value: (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.O.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1.[OH-].[Na+]>CN(C)C=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:20])[CH2:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of 15.4 g. of acetonine in 100 ml. of dimethylformamide was added with 19.0 g. of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 8 hours, then allowed to stand overnight to complete the reaction. After completion of the reaction, the reaction mixture was added with 30% aqueous sodium hydroxide solution and extracted with ether. The extract was dried over anhydrous potassium carbonate and ether was distilled off. The resulting residue was purified by distillation under reduced pressure to obtain triacetonamine in a yield of 88.8%.
Reaction SMILES: [CH2:1]([C:3]([CH2:14][CH3:15])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[C:4]([NH2:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:14]([C:3]([CH2:1][CH3:2])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH2:6])=[O:5])[CH3:15]
Reactant: BrCc1ccccc1
Reactant: CCC(CC)(C(N)=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of α,α-diethyl-2-hydroxy-benzeneacetamide (Example 266b, 1.21 g) in DMF (9.93 mL) was treated with potassium carbonate (0.807 g) and benzyl bromide (0.694 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography eluting with 30-100% ethyl acetate in iso-hexane) to afford the subtitle product (0.77 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1.I[CH2:12][CH3:13]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[N:8]([CH2:12][CH3:13])[CH:9]=1
Reactant: CCI
Reactant: Oc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.34 g, 0.056 mol) in THF (10 mL), a solution of 5-bromopyridin-2-ol (2.5 g, 0.014 mol) in THF (50 mL) was added and the resulting mixture was stirred at RT for 1 h. To this mixture, iodoethane (10.9 g, 0.07 mol) was added and the mixture was stirred at RT overnight. The mixture was quenched with water and washed with NH4Cl solution. The organic phase was separated, then concentrated in vacuo and the residue was purified by flash chromatography on silica gel (50-100% PE-AE) to afford 5-bromo-1-ethylpyridin-2(1H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Yield: 99 %

Procedure:
A solution of 2-methyl-5-nitrobenzoic acid (1.51 g, 8.34 mmol) and H2SO4 (catalytic) in MeOH (20 mL) was heated at reflux for 17 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (40 mL), washed with saturated NaHCO3(aq) (30 mL), then dried (MgSO4) and concentrated in vacuo to give yellow crystals (1.62 g, 99%). 1H NMR (CDCl3) δ 2.72 (s, 3H), 3.96 (s, 3H), 7.44 (d, 1H, J=8.7 Hz), 8.24 (dd, 1H, J=8.7, 2.7 Hz), 8.78 (d, 1H, J=2.7 Hz).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CO>[CH2:15]([N:9]1[C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH3:3])[C:12]=2[N:11]=[CH:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A 10% aqueous sodium hydroxide solution (10 ml) was added to a suspension of 3-methylxanthine (4.15 g) in methanol (25 ml) and the mixture was stirred for 1 hour at 70° C. Benzyl bromide (4.275 g, 2.97 ml) was added dropwise at 70° C. and the mixture was stirred at 70-80° C. for an additional 5 hours. After cooling to room temperature, the mixture was treated with water (50 ml). The precipitate was filtered, dissolved in 1 N aqueous sodium hydroxide solution (50 ml) and the solution was acidified to pH 4-5 with concentrated hydrochloric acid. The precipitate was filtered and washed with water (3×20 ml) to provide 7-benzyl-3-methylxanthine (4.45 g).
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.N(OC(C)(C)C)=O.O.C(Cl)[Cl:19]>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:19])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: ClCCl
Reactant: Nc1ncc(Br)nc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)(C)ON=O
Solvent: O
Product: Clc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (234 g, 932 mmol) in DCM (700 mL) and titanium (IV) chloride (174 g, 926 mmol), tert-butyl nitrite (572 g, 5.55 mol) was slowly added. The resulting mixture was stirred for 2 h at room temperature and treated with water (500 mL). The resulting mixture was extracted with DCM (3×500 mL). The combined organic layers were concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:50 v/v)) to obtain compound 90d as colorless oil (210 g, 83% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C4HBr2ClN2: 272.8 (M+H). found 272.6.
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[C:21]([Br:22])=[CH:20][C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[C:10]=1[Br:23].CCOCC>CN(C=O)C>[Br:23][C:10]1[C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH:20]=[C:21]([Br:22])[CH:9]=1
Reactant: Nc1c(Br)cc2oc3ccccc3c2c1Br
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1cc(Br)c2c(c1)oc1ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 116.4 %

Procedure:
To a solution of t-butylnitrite (0.89 ml, 7.2 mmol) dissolved in 10 ml of DMF at 50° C. was added dropwise a solution of 2-amino-1,3-dibromodibenzofuran 10 (1.0 g, 2.9 mmol) in 10 ml of DMF with nitrogen evolution. After stirring at 50° C. for 1 hour the reaction was diluted into ether and washed successively with H2O and saturated NaCl. Drying over MgSO4 and evaporation gave 1.1 g of a red solid which was purified by flash chromatography through 100 g of silica gel (20% methylene chloride:hexane) yielding 650 mg (68%) of the title compound as a pale orange solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:14][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCNCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A mixture of 6-bromo-2-pyridinecarboxaldehyde (54) (20 g, 108 mmol) and 2-methoxy ethanamine (10.3 mL, 8.88 g, 118 mmol) in DCM (1.3 L) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (25 g, 118 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water (400 mL) and acidified to pH=4 with 1M HCl (−140 mL). The two phases were separated and the organic layer was extracted with 0.25M HCl (2×500 mL). The aqueous layers were combined, basified to pH=9 with 4N NaOH, extracted with DCM (1×500 mL), dried over Na2SO4, filtered and concentrated yielding 25.2 g of 55 (96%). MS (m/z): 245.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:20]1([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:15]2[CH2:18][C:17](=[O:19])[CH2:16]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Yield: 98.8 %

Procedure:
Triethylamine (112.1 g, 1.11 mols) was added to a solution of N-diphenylmethylazetidin-3-ol (26.6 g, 0.11 mol) in DMSO (300 ml). The solution was cooled to 10° C. and a solution of sulphur trioxide-pyridine complex (112 g, 0.7 mol) in DMSO (500 ml) added, rapidly. Stirring was continued at 10° C. for 0.75h and the mixture then warmed to 25° C. and stirred for 1h. The solution was poured into ice-water (21) and extracted with EtOAc (3×1). The combined extracts were washed with water (500 ml) and brine (500 ml) and dried (Na2SO4). The crude product was purified by chromatography through silica-gel eluting with petroleum ether/EtOAc (2:1) to give the desired ketone (25.8 g), mp 74°-75° C.; δ (360 MHz, CDCl3) 4.00 (4H, s, 2 of CH2), 4.59 (1H, s, CH), 7.19-7.49 (10H, m, Ar--H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)(=O)C.CC(C)=O>[CH3:16][O:15]/[N:14]=[C:9](\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH3:17])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
A mixture of (E)-2-(2-chloromethylphenyl)-2-methoxyimino-N-methylacetamide (500 mg), 2,5-dimethylphenol (700 mg), potassium carbonate (700 mg), potassium iodide (500 mg) and acetone (5.0 ml) was heated under reflux with stirring for 6 hours. After the mixture was cooled by allowing it to stand, ethyl acetate was added to the reaction mixture. The mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (ethyl acetate:hexane=2:1) to obtain the title compound (530 mg, 78%). This compound was crystallized from diethyl ether-hexane to obtain the title compound as crystals (430 mg, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:17][C:18]#[N:19].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]#[N:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Reaction time: 4 h

Procedure:
To a partially dissolved solution of piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 10 mmol) in THF (30 mL) is added 60% NaH (0.44 g, 11 mmol). The resulting solution is stirred for 5 min before the addition of bromoacetonitrile (0.9 mL, 13 mmol). The reaction is stirred for 4 h. MeOH (1 mL) is added and the solution is concentrated and the residue is diluted with EtOAc, washed with 1 N HCl, H2O, NaHCO3 and the solution is dried over MgSO4. The filtrate is concentrated and the crude product is chromatographed using a silica column (50% EtOAc/PE-EtOAc) to yield 4-cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3) δ4.41 (s, 2H), 4.16 (s, 2H), 3.75 (t, 2H), 3.51 (t, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:28])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A mixture of 50 g of p-(tetradecyloxy)benzoic acid and 28.46 g of oxalyl chloride in 500 ml of chloroform containing 10 drops of N,N-dimethylformamide is stirred for 18 hours at ambient temperature. The solvent is evaporated and the residue dissolved in ether, filtered and evaporated to give 54 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: C1CCNC1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC1(C)CN(CC(=O)N2CCCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 82 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and pyrrolidine in 82% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.21 (s,3H), 1.29 (s,3H), 1.75-1.92 (m,4H), 2.46 (d,1H), 2.77 (d,1H), 3.35-3.68 (m,7H), 3.94 (m,2H), 8.08 (s,1H), 8.19 (d,1H), 8.23 (s,1H), 8.41 (d,1H), 9.05 (s,1H), 10.71 (s,1H), 11.51 (s,1H). Retention Time (LC, method: ammonium acetate standard): 1.75 min. MS (M+H+): 470.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16]>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and 1-dimethylamino-2-methylamino-ethane
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCC(C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(C(=O)Cl)CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 578.2 g of 4-carboxy-1-ethoxycarbonylpiperidine in 1200 ml of toluene is treated firstly with 1.0 g of N,N-dimethylformamide and then, at from 68° to 70° C. and within the space of 2 hours, with 369.0 g of thionyl chloride. The mixture is subsequently stirred at 70° C. for a further 30 min, after which the toluene is distilled off in vacuo and the residue is then degassed at RT for approximately 30 min under HV. This results in the title compound in the form of a weakly yellow oil [IR (Film): 2960, 2870, 1790, 1695, 1470, 1435, 1300, 1230, 1130, 960, 765 cm-1 ]. The product distils without decomposition at a m.p. of 96°-98° C. (0.08-0.09 Torr).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O>[N+:18]([C:14]1[C:10]2[C:11](=[O:13])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:1](=[O:8])[C:9]=2[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 2-benzoyl-6-nitrobenzoic acid (2.0 grams; 0.0074 mole) in 10 mls. of concentrated sulfuric acid (99.5% by weight) was stirred at 100° C for 3 hours, then cooled to room temperature and poured into a mixture of ice and water. The resulting mixture was filtered to recover the precipitated solids. The filter cake was then washed successively with a dilute aqueous solution of sodium carbonate and water, and dried to obtain 1-nitroanthraquinone (1.59 grams; 85% yield). The product was identified by comparison of its vapor phase chromatographic spectrum with that of an authentic sample.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[S:13][C:2]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2ccc(F)cc2s1
Yield: 67.3 %

Procedure:
Using 2.00 g (14.07 mmol) of 2,4-difluorobenzaldehyde, 0.84 g (21.11 mmol) of sodium hydride (60% pure) and 1.64 g (15.48 mmol) of methyl mercaptoacetate, 1.99 g of the desired product are obtained. The product is obtained in a purity which permits further reaction and is reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (5.11 g, 23.8 mmol, 1.0 equiv) in methanol (25 mL) was added dropwise ulfuric acid (2.0 mL) over about 3 minutes (mildly exothermic). The resulting mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was carefully quenched into saturated aqueous NaHCO3 (100 mL) (note—significant gas evolution) and extracted with dichloromethane (200 mL×1 then 50 mL×1). The combined organic phases were washed with a mixture of brine/saturated NaHCO3 (9:1)(50 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain the title compound as a colorless oil (5.28 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=8.0 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.38 (dd, J=1.6 Hz, 1H), 3.89 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][OH:14].[OH-].[Na+].O>C(Cl)Cl>[C:1]([O:14][CH2:13][CH2:12][N:11]([CH3:15])[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C)CCOC(=O)c1ccccc1
Reaction time: 3.25 h
Yield: 61.6 %

Procedure:
A solution of 70.29 g (0.50 mol) of benzoyl chloride in 500 ml of methylene chloride was added to a solution of 44.57 g (0.50 mol) of 2-dimethylaminoethanol, 20.0 g (0.50 mol) of sodium hydroxide and 500 ml of water over 15 minutes with rapid stirring. Stirring was continued for 3.25 hours after which the organic layer was separated, washed with water, dried over MgSO4 and concentrated. Distillation of the residue gave 59.5 g of product; bp=102°-8° C./0.50 mm.