Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].C([O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)(=O)C>O>[CH:8]([C:29]1[N:25]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=2[OH:14])[C:19]([O:21][CH3:22])=[O:20])[CH:26]=[CH:27][CH:28]=1)=[O:9]
Reactant: COC(=O)c1ccc(OC(C)=O)c(-n2cccc2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(O)c(-n2cccc2C=O)c1
Reaction time: 20 h

Procedure:
To a solution of phosphorus oxychloride (8.3 ml) and N,N-dimethylformamide (70 ml) was added methyl 4-acetoxy-3-(pyrrol-1-yl)benzoate (11.7 g) at ambient temperature and the mixture was stirred for 20 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tetrahydrofuran. To the solution was added 28% methanolic sodium methoxide (9.7 ml) under ice-cooling and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added acetic acid (6 ml) and evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and adjusted to pH 7 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from toluene, collected by filtration and the precipitate was washed with ether to give methyl 3-(2-formylpyrrol-1-yl)-4-hydroxybenzoate (7.89 g).
Reaction SMILES: C([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=O.[CH2:11]([N:13](CC)CC)C.ClC(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N+:13]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[C-:11]
Reactant: CCN(CC)CC
Reactant: O=CCCCCCC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: [C-]#[N+]CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of the above 6-formyl hexanoic acid Wang-resin ester (165 g, 0.16 mol) in dichloromethane (3.2 l) was added triethylamine (222 ml, 1.6 mol), tetrachloromethane (155 ml, 1.6 mol) and triphenylphosphine (168 g, 0.64 mol). The resulting mixture was stirred at room temperature for 16 h under an atmosphere of nitrogen. The resin was filtered off and washed with N,N-dimethylformamide, dichloromethane, methanol, dichloromethane and dried in a vacuum desiccator for 18 h which afforded 6-isocyano-hexanoic acid Wang-resin ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:37])=[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=3)[CH2:19][CH2:20][CH3:21])[C:13]=2[CH3:37])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(F)cc2)c1C

Procedure:
Prepared from 4-fluorophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=2)[N:10]=1
Reactant: O=c1[nH]c(-c2cccc(C(F)(F)F)c2)cs1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2csc(Cl)n2)c1
Yield: 64.8 %

Procedure:
A mixture of 24.55 g (100.1 mmole) of 4-(3-trifluoromethyl-phenyl)-3H-thiazol-2-one and 75 mL (0.811 mole) of phosphorus oxychloride was heated at reflux for 3 hours. The cooled mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and poured onto ice. The mixture was made basic by the addition of saturated sodium carbonate solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-20:80) to give 17.09 g of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)=[O:11])#[N:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)=[O:11])#[N:2]
Reactant: COC(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cccc(OCCNC(=O)c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
310 mg (1 mmol) of methyl 4-[N-[2-(3-cyanophenoxy)ethyl]carbamoyl]benzoate was stirred in 15 ml of ethanol and 15 ml of THF. 3 ml of 1 N aqueous sodium hydroxide solution was added thereto and they were stirred at room temperature overnight. The reaction liquid was distilled under reduced pressure and then 1 N hydrochloric acid was added to the residue. After the extraction with ethyl acetate, the extract was washed with a saturated aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1occc(=O)c1OCc1ccccc1

Procedure:
3-Hydroxy-2-methyl-4-pyrone (22.2 g) in methanol (225 ml) is added to aqueous sodium hydroxide (25 ml H2O containing 7.5 g NaOH). Benzyl chloride (25.5 g) is added and the mixture is refluxed for 6 hours and is then allowed to cool overnight. The bulk of the methanol is removed under vacuum and the residue is treated with water (50 ml). The mixture is extracted into dichloromethane (3×25 ml). The extracts are combined, washed with 5% w/v NaOH (2×25 ml), then water (2×25 ml) and dried over magnesium sulphate. Evaporation of the solvent gives crude 3-benzyloxy-2-methyl-4-pyrone or "benzyl maltol" (35 g, 92%) which is purified by distillation in nitrogen under reduced pressure to yield a colourless oil (28 g) of b.p. 148° C./0.2 mm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13](C(O)=O)[NH:12]2)=[O:10])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][N:26]([C:29](C2C=CC(N)=CC=2)=[O:30])[CH2:25]1.[CH2:38]([Cl:41])[CH2:39]Cl>CN(C=O)C>[O:24]1[CH2:28][CH2:27][N:26]([C:29]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH:11]3[CH2:20][C:15]4[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13][N:12]3[C:9]([NH:8][C:5]3[CH:6]=[CH:39][C:38]([Cl:41])=[CH:3][CH:4]=3)=[O:10])=[O:10])=[CH:6][CH:7]=2)=[O:30])[CH2:25]1
Reactant: ClCCCl
Reactant: Nc1ccc(C(=O)N2CCOC2)cc1
Reactant: O=C(O)C1Cc2ccccc2C(C(=O)Nc2ccc(Cl)cc2)N1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCOC2)cc1)C1Cc2ccccc2CN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of 2N-(4-chlorophenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (50 mg, 0.15 mmol) and 4-(3-oxazolidinylcarbonyl)phenylamine (25 mg, 0.13 mmol) in DMF (3 mL), EDC (75 mg, 0.39 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (26 mg). MS 505.2 and 507.2 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3](=[O:20])[CH:2]([NH:1][C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
A solution of 3(R,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.0 g) in anhydrous tetrahydrofuran (20 ml) under an atmosphere of nitrogen at 0° C. was treated with triethylamine (0.51 ml), followed by a solution of 4-nitrophenyl chloroformate (0.75 g) in anhydrous tetrahydrofuran (10 ml) dropwise. After stirring at ambient temperature for 20 min, the solid which precipitated from the mixture was filtered and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (1.2 g, 75%) as a colourless solid. Mp 165°-168° C. 1H NMR (360 MHz, CDCl3) δ 1.05 (1H, m), 1.18-1.42 (3H, m), 1.55 (1H, m), 1.65 (3H, m), 1.87 (1H, m), 2.05 (1H, m), 2.80 (1H, m), 3.43 (3H, s), 5.18 (1H, d, J=8.3 Hz), 6.90 (1H, d, J=8.2 Hz), 7.30 (4H, m), 7.57 (2H, m), 8.23 (2H, d, J=7.1 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]1[O:21][C@H:20]1[CH2:22][OH:23]>CC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:19][C@@H:20]([OH:21])[CH2:22][OH:23])=[CH:10][CH:11]=1
Reactant: OCCCCc1ccc(O)cc1
Reactant: OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCc1ccc(OC[C@@H](O)CO)cc1

Procedure:
To 4-(4-Hydroxy-butyl)-phenol (32.7 g, 197 mmol) in acetone (600 ml) is added potassium carbonate (40.8 g, 295 mmol) followed by (S)-glycidol (13.7 ml, 207 mmol). The mixture is heated at reflux overnight. Further potassium carbonate (20 g) is added, followed by (S)-glycidol (5 g) and the mixture is heated at reflux for 72 hours. The suspension is cooled, filtered and the filtrate concentrated in vacuo. The residue is partitioned between EtOAc (500 ml) and 5% citric acid solution (500 ml). The organics are separated, dried (MgSO4) and concentrated in vacuo to give (S)-3-[4-(4-Hydroxy-butyl)-phenoxy]-propane-1,2-diol as a brown oil; 1H NMR (CDCl3): 1.56-1.74 (4H, m), 2.20 (1H, t, J=2.46 Hz), 2.61 (2H, t, J=7.6 Hz), 3.68 (2H, t, J=6.2 Hz), 3.78 (1H, dd, J=5.4 and 11.5 Hz), 3.86 (1H, dd, J=3.9 and 11.5 Hz), 4.0-4.16 (3H, m), 6.85 (2H, d, J=8.6 Hz), 7.12 (2H, d, J=8.6 Hz).
Reaction SMILES: CI.[CH2:3]1CCN2C(=NCCC2)CC1.[OH:14][C@@H:15]1[CH2:19][C@H:18]([OH:20])[C@H:17]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[C@H:16]1/[CH:34]=[CH:35]/[C@@H:36]([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CC(C)=O.CCOC(C)=O>[OH:14][C@@H:15]1[CH2:19][C@H:18]([OH:20])[C@H:17]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][C:27]([N:29]([CH3:3])[S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[C@H:16]1/[CH:34]=[CH:35]/[C@@H:36]([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)NS(C)(=O)=O)[C@@H](O)C[C@H]1O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)N(C)S(C)(=O)=O)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl iodide (38 μL, 0.61 mmol) and DBU (45 μL, 0.30 mmol) were added to a solution of N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}methanesulfonamide (44 mg, 0.10 mmol) in acetone (1.5 mL). After stirring for 2.5 h at room temperature, the reaction was diluted with EtOAc, washed with water (2×) and brine then concentrated in vacuo to afford the title compound. See FIG. 1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7](C([Cl:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[ClH:12].[C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(=O)Cl)CC1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1CCNCC1
Product: Cl

Procedure:
1-Acetyl-4-chlorocarbonylpiperazine can be prepared by the action of phosgene (9.9 g.) on 1-acetylpiperazine (25.6 g.) in anhydrous toluene (75 cc.) for 1 hour at 2° C. The 1-acetylpiperazine hydrochloride formed during the reaction is filtered off and washed with anhydrous toluene (50 cc.). The toluene filtrate is evaporated to dryness under reduced pressure (20 mm.Hg) to give 1-acetyl-4-chlorocarbonylpiperazine (14.0 g.) in the form of an oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:20]=[C:21]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:22][C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:56]1([NH:62][C:63]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][CH:64]=2)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C=O)C.O>[O:20]=[C:21]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:30][CH2:31]1)[CH2:22][C:23]([NH:69][C:66]1[CH:65]=[CH:64][C:63]([NH:62][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:68][CH:67]=1)=[O:25]
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(Nc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
HOBt (70 mg, 0.5 mmol) and DIEA (11 mg, 0.9 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (50 mg, 0.3 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (80 mg, 0.5 mmol) followed by N-phenyl-benzene-1,4-diamine (100 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using basic alumina (10% methanol in chloroform) to afford 15 mg (10%) of 3-oxo-N-(4-phenylamino-phenyl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 511.19 (M+1)+, 96.55%, 1H NMR: (CDCl3): δ 7.7 (m, 1H), 7.6 (m, 2H), 7.4 (m, 4H), 7.1 (m, 1H), 7.0 (m, 3H), 6.8 (m, 1H), 4.0 (m, 2H), 3.8 (m, 2H), 3.4 (m, 3H), 3.2 (m, 2H).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[O:6]1C=[CH:9][CH:8]=[C:7]1[NH:11][CH2:12][C:13]#[N:14].[CH3:15][N:16]1[CH:20]=C(C(Cl)=O)C=[N:17]1>C(N(CC)CC)C>[C:13]([CH:12]([C:3]1[O:4][CH:5]=[CH:1][CH:2]=1)[NH:11][C:7]([C:8]1[CH:9]=[N:17][N:16]([CH3:20])[CH:15]=1)=[O:6])#[N:14]
Reactant: C1CCOC1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: N#CCNc1ccco1
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NC(C#N)c2ccco2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a THF solution containing the α-(2-furyl)aminoacetonitrile (2.15 g) and triethylamine (1.75 g) was added 1-methyl-1H-pyrazole-4-carboxylic acid chloride (2.55 g) under cooling with ice, and the whole was stirred for 1 hour as such and then for 16 hours at room temperature. The solid product formed was taken out by filtration, and the solvent was evaporated out, and then the thus-obtained oily product was purified by column chromatography and then washed with isopropyl ether, to give 2.55 g of the intended N-(cyano-2-furanylmethyl)-1-methyl-1H-pyrazole-4-carboxamide crystal.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C.O>[CH2:10]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([Cl:9])=[C:2]([Br:1])[N:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Cl)c(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: Clc1ccc(NCc2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 11A (500 mg, 2.410 mmol) in 1,2-dichloroethane (10 mL) and acetic acid (5 mL) was treated with benzaldehyde (281 mg, 2.65 mmol) and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (2.043 g, 9.64 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (25 mL), treated with saturated sodium bicarbonate solution, extracted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude title compound. Purification by column chromatography (silica gel, 15% ethyl acetate in hexane) afforded the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Br)=[CH:7][C:6]=1[N+]([O-])=O)(=[O:3])C.[OH-].[Na+].BrC1C2C(=CC=CC=2)C(O)=C([N+:33]([O-])=O)C=1>>[NH2:33][C:1]([NH2:4])=[O:3].[N:4]1[C:5]2[C:14]3[C:9]([CH:8]=[CH:7][C:6]=2[O:3][CH:1]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2ccccc12
Reactant: O=[N+]([O-])c1cc(Br)c2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: NC(N)=O
Product: c1ccc2c(c1)ccc1ocnc12

Procedure:
When 1-(acetylamino)-4-bromo-2-nitronaphtalene was treated with aqueous sodium hydroxide as described above the product was 4-bromo-2-nitro-1-naphtol—i.e. substitution occurred instead of hydrolysis. Subsequent hydrogenation and treatment with urea yielded naphto[1,2-d]oxazoline in 44% overall yield.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[O:15]C(C)(C)[O:13][C:11](=O)[CH:10]=1>C1(C)C(C)=CC=CC=1>[C:11]([N:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:11](=[O:13])[CH2:10][C:9]([CH3:8])=[O:15])[CH2:3][CH2:2]1)(=[O:13])[CH2:10][C:9]([CH3:8])=[O:15]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: C1CNCCNC1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCCN(C(=O)CC(C)=O)CC1
Temperature: 124 °C
Yield: 96.2 %

Procedure:
To 1,4-diazacycloheptane (81.90 g, 0.819 mol) in xylene (525 ml) at 122° C. was added with stirring 2,2,6-trimethyl-1,3-dioxen-4-one (232.49 g, 1.637 mol) in xylene (525 ml) over 10 minutes, during which the temperature decreased to 99° C. After heating to 124° C. over 5 minutes vigorous effervescence commenced, and after heating to 127° C. over 5 minutes distillation of acetone (through a Vigreux column) also commenced. Pot temperature was increased to 140° C. over a further 30 minutes, with collection of acetone distillate. After cooling to 15° C. overnight, supernatant liquid was separated from deposited syrup, which was dissolved in dichloromethane. Removal of solvent from combined solutions and drying (91° C./100 Pa) gave N,N′-bis(acetoacetyl)-1,4-diazacycloheptane (BAADCH) as a viscous syrup (211.16 g, 96%), identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:24]2[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=2[F:34])[C:19]([O:21]CC)=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O.C(#N)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:35])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:24]2[C:25]([F:34])=[C:26]([F:33])[C:27]([F:32])=[C:28]([F:31])[C:29]=2[F:30])[C:19]([OH:21])=[O:20])=[O:15])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CNC(=O)CCC(=O)Nc1ccc(C=NN)cc1)c1c(F)c(F)c(F)c(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: NN=Cc1ccc(NC(=O)CCC(=O)NCC(C(=O)O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
Ethyl β[[4-[[4-(aminoiminomethyl)phenyl]-amino]-1,4-dioxobutyl]amino]-(pentafluorophenyl)propanoate prepared in Example 59 (600 mg) was added to water/acetonitrile (20 ml) followed by lithium hydroxide (100 mg) at 25° C. The mixture was stirred for 30 min. The course of the reaction was monitored by RPHPLC. After satisfactory acid was formed the reaction was neutralized with TFA and purified by reverse phase chromatography (water/acetonitrile) to result in 620 mg of a white solid: 1H NMR (d6 -DMSO) δ2.38 (t, 2H, J=7.3 Hz), 2.44 (d, 2H, J=6.4 Hz), 2.56 (t, 2H, J=7.3 Hz), 4.32 (m, 1H), 7.78 (s, 4H), 7.99 (d, 1H,J=8.1 Hz), 8.92 (bs, 2H), 9.16 (bs, 2H), 10.39 (s, 1H); MS (FAB) m/z 365.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.Cl.[NH2:16]O.C([O-])=O.[Na+]>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]#[N:16]
Reactant: NO
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
28.1 parts of 3,7-dichloro-8-chloromethylquinoline (Example 1), 6.95 parts of hydroxylamine hydrochloride and 13.6 parts of sodium formate in 200 ml of formic acid and 60 ml of water were stirred at 100° C. for 12 hours. The reaction solution was poured onto ice and the precipitated solid was filtered off with suction, washed neutral with water and dried. 19 parts of 3,7-dichloro-8-cyanoquinoline of melting point 222° C. were obtained. The yield corresponds to 78.5% of theory.
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[CH3:25][C:26](=[CH:28][CH2:29][CH2:30][C:31](=[CH:33][CH:34]=[O:35])C)C.O>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:34]([OH:35])[CH:33]=[CH:31][CH2:30][CH2:29][CH:28]=[CH:26][CH3:25])[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(Cn2ccnc2)c1
Reactant: CC(C)=CCCC(C)=CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC=CCCC=CC(O)C(c1cccc(Cl)c1)n1ccnc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
26 ml (40 mmol) of 1.55 molar n-butyllithium/hexane solution were added dropwise to a solution of 7.70 g (40 mmol) of N-(3-chlorobenzyl)-imidazole in 100 ml of absolute THF at -70° C. in the course of 15 minutes. The mixture was stirred for 30 minutes at -70° C., after which a solution of 6.10 g (40 mmol) of citral (cis/trans mixture) in 50 ml of absolute THF was added dropwise at -70° C., stirring was continued for 45 minutes at about -70° C., the mixture was allowed to warm up to room temperature in the course of about 2 hours, 300 ml of water were added, while cooling, and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated down in vacuo. The residue (13.2 g) from the extract was chromatographed over a silica gel S/n-hexane column (diameter 2.5 cm, height 56 cm), with elution with hexane/ethanol mixtures having an increasing ethanol content (up to a maximum of 20% of ethanol). The course of the elution was monitored by means of thin layer chromatography. This showed that the desired compound was present in the form of 4 stereoisomers in similar amounts. Fractions which were shown to be pure by thin layer chromatography were combined and evaporated down in vacuo until the weight remained constant. In this way, 1.2 g of virtually pure stereoisomer (a), having the highest Rf value, were obtained. In addition, 8.2 g of a mixture of the stereoisomers (b), (c)≥(a), (d) were obtained. Finally, 2.6 g were eluted, which were found by thin layer chromatography to contain a high concentration of the stereoisomer (d) (lowest Rf value). This product was subjected to a second chromatography by the same procedure, over a silica S/hexane column (diameter 2 cm, height 22 cm). 1.2 g of a stereoisomer (d) which was shown to be virtually completely pure by thin layer chromatography was obtained.