Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]1([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14](O)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>C1C=CC=CC=1>[C:2]1([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([Cl:27])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)O
Agent: [Na]
Solvent: c1ccccc1
Product: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a suspension of 12 g of the sodium salt of α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid in 200 ml of absolute benzene are added with stirring at 5°C 25 g of oxalyl chloride. The mixture is continuously stirred overnight at room temperature, then evaporated to dryness in vacuo. The residue is dissolved in 200 ml of absolute benzene are added with stirring at 5° C 25 g of oxalyl chloride. The mixture is continuously stirred overnight at room temperature, then evaporated to dryness in vacuo. The residue is dissolved in 200 ml of absolute benzene and filtered under anhydrous conditions. The filtrate is evaporated to dryness in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid chloride, which is used directly for further processing.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27]>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH:27][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Product: COc1ccc(C)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 5-methoxy-2-methylaniline (19 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (21 mg, 61%). 1H NMR (CDCl3): 8.88-8.86 (m, 1H), 8.71-8.60 (m, 3H), 7.92-7.83 (m, 2H), 7.62 (s, 1H), 7.44-7.34 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 7.06 (s, 1H), 6.78 (dd, J=2.4, 8.4 Hz, 1H), 3.82 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[C:33]([NH2:35])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1.Cl.C(N=C=N)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[C:33]([NH:35][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:34]=[C:25]([C:24]([O:23][CH3:22])=[O:36])[CH:26]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)cc(C(=O)OC)c1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a mixture of (4-adamantan-1-yl-phenoxy)-acetic acid (143.2 mg, 0.50 mmol), 5-aminoisophthalic acid dimethyl ester (156.9 mg, 0.75 mmol), N-3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 mL) was added N,N-disopropylethylamine, redistilled (DIPEA) (0.13 mL, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=9:3:1) to give 5-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester as a light yellow solid (195.6 mg, 81.92% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][CH2:14][C@@H:15]([CH3:18])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][C@H:15]([CH3:18])[CH2:14][Br:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: C[C@@H](CO)CBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(OC[C@H](C)CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.75 g, 0.0045 mole) in anhydrous toluene (30 mL) was added (S)-(+)-3-bromo-2-methyl-1-propanol (0.90 g, 0.0059 mole). Polymer bound triphenylphosphine (2.4 g, 0.0072 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture was stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.1 g, 0.00560 mole) was added In a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered, and the solid washed with toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 0.86 g (63% yield) of the title compound as an oil: MS (ESI) 303.0 (M+2H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:10]=[C:11](F)[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([F:15])[CH:14]=1>C1COCC1>[Br:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH:10]=1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(Br)cc1-n1cccn1
Temperature: 0 °C
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (44 mg, 1.1 mmol, 60% oil dispersion) in THF (4 mL), stirred at 0° C., was added a solution of pyrazole (72 mg, 1.05 mmol) in THF (1 mL). The resulting mixture was stirred at 0° C. for 5 minutes and a solution of 5-bromo-1,3-difluoro-2-nitro-benzene (238 mg, 1 mmol) in THF (1 mL) was added. The mixture was stirred at room temperature for 1 hour, quenched by addition of water (1 mL), then partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with ethyl acetate:hexanes (1:6), to afford 240 mg (86%) of the title compound. 1H NMR (CDCl3) δ 6.55 (t, 1H), 7.45 (d, 1H), 7.60 (s, 1H), 7.80 (m, 2H). MS M+1 287, M+1+2 289.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([C:5]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[S:1](=[O:3])(=[O:2])[NH:4]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=S1(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc21

Procedure:
Various procedures have been reported for synthesizing 3-substituted-benz[d]isothiazole-1,1-dioxides and 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxides from saccharin (3-oxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide) and from saccharin pseudo-chloride (3-chlorobenz[d]isothiazole-1,1-dioxide). As reported by A. Mustafa et al, J. Chem. Soc., 1952, p. 1339, the treatment of saccharin pseudo-chloride with excess phenylmagnesium bromide gave the corresponding 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide in almost quantitative yield. Methyl-, ethyl-, n-propyl- and n-butylmagnesium halides were reported by these authors to react analogously. R. A. Abramovitch et al, J. Chem. Soc., Perkin Trans I, 1974 (22), p. 2589, reviewed and reinvestigated the reactions of saccharins with alkyl and aryl Grignard reagents and found that either the 3-alkyl (or 3-aryl)-benz[d]-isothiazole-1,1-dioxide and/or the open-chain tertiary alcohol, o--CH2OH benzenesulfonamide wherein R is alkyl (or aryl) were obtained with one exception. When saccharin was treated with an excess of phenylmagnesium bromide in boiling tetrahydrofuran, 3,3-diphenyl-2,3-dihyrobenz[d]isothiazole-1,1-dioxide was obtained as the minor product together with the open-chain tertiary alcohol.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[CH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[O:4][N:3]=1>CCOC(C)=O.CO.[Pd]>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C=CCCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCCCc1ccccc1
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-but-1-enyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.030 g, 0.07 mmol) was dissolved in EtOAc and MeOH. 10% Palladium on carbon (spatula tip) was added, and the reaction was stirred under a balloon of H2 overnight. The mixture was filtered and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]C)=[CH:12][CH:13]=2)[C:8]([OH:17])=[N:7]1.Br.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[C:8]([OH:17])=[N:7]1
Reactant: COc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1

Procedure:
4.85 g 1-(3,4-dichlorobenzyl)-5-methoxy-1H-indazole-3-ol are heated in 30 ml acetic acid and 30 ml 50% hydrobromic acid for 4 hours under gentle reflux. After cooling, the mixture is stirred into 250 ml water, rendered alkaline with concentrated sodium hydroxide solution and extracted twice with 80 ml tert-butyl methyl ether. The aqueous phase is acidified with sulfuric acid and extracted by shaking three times with 200 ml tert-butyl methyl ether. The combined ether phases are dried over sodium sulfate and distilled to dryness under vacuum. The residue is washed with a small amount of tert-butyl methyl ether and dried.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[Br:20]Br>ClCCl>[Br:20][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[CH:2]([OH:1])[C:7]([CH3:8])([CH3:9])[O:6][C:5]=2[CH:10]=1
Reactant: BrBr
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 4 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.4 g, 5.0 mmol) and bromine (0.27 mL, 5.2 mmol) in dichloromethane (30 mL). Purification by flash chromatography using 1% methanol in dichloromethane as the eluant and recrystallization from dichloromethane/hexanes gave the product, 3.87 g (78%), as a colorless solid: mp 200°-202° C.; IR(KBr): 3442, 2942, 1616, 1571 and 1488 cm-1 ; MS: m/z 360 (MH+); 1H NMR(CDCl3): δ 1.29 (s, 3H), 1.46 (s, 3H), 1.82 (m, 4H), 2.51 (m, 2H), 3.12 (m, 1H), 3.27 (m, 1H), 3.46 (d, J=5.0 Hz, 1H, exchanges with D2O),3.78 (d,d, J=9.0 Hz, J=5.0 Hz,1H, simplifies to d, J=9.0 Hz, with D2O), 5.74 (d, J=9.0 Hz, 1H) and 7.58 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:20][CH2:19][C:14]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.BrC1NC2N=CN=C([C:30]3[C:31]([CH3:49])=[C:32]([NH:36][C:37](=[O:48])[C:38]4[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=4)[CH:33]=[CH:34][CH:35]=3)C=2C=1>>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([C:37]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH2:20][CH2:19][C:14]6([O:18][CH2:17][CH2:16][O:15]6)[CH2:13][CH:12]=5)[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[C:31]=2[CH3:49])=[O:48])=[CH:39][CH:40]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Clc1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(Br)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12

Procedure:
Example 65 was prepared analogue to Intermediate 17 by replacing 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine with Intermediate 54.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COc1cccc(CBr)c1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Product: CNC(=O)C=Cc1ccc(OCc2cccc(OC)c2)cc1
Yield: 60 %

Procedure:
The title compound is prepared in analogy to example 11 b) from 3-(4-hydroxy-phenyl)-N-methyl-acrylamide and 1-bromomethyl-3-methoxy-benzene. Yield=60%. Colorless solid. MS: m/e=298.2 (M++H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
6-Chloropyridin-3-ol (30.00 g, 231.6 mmol), 1-(bromomethyl)benzene (43.57 g, 254.7 mmol), and potassium carbonate (80.01 g, 579.0 mmol) were added to DMF (500 mL) and stirred at ambient temperature overnight. Water was added and extracted with ether. The organic phase was washed with 1M NaOH, dried, filtered, and concentrated to provide the title compound (50.8 g, 99.86% yield).
Reaction SMILES: [NH2:1][C:2](=[O:34])[CH2:3][N:4]([S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6]1=[O:19].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2](=[O:34])[CH2:3][N:4]([S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH3:18])[C:11]([OH:13])=[O:12])[C:6]1=[O:19]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(CC(N)=O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)O)N1CC[C@H](N(CC(N)=O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
tert-Butyl (2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1.4 g) was dissolved in DCM (35 ml), and trifluoroacetic acid (35 ml) was added. The mixture was stirred at room temperature for 2 h and then evaporated under reduced pressure. The residue was azeotroped with anhydrous dichloromethane and then dried under high vacuum. The residual viscous oil was triturated with diethyl ether to give the title compound (1.23 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(CO)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(=O)OCC(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
3.7 g of 3-[4-(tert-butyloxycarbonyl)-1-piperazinyl]-2,2-dimethylpropanol and 30 mg of 4-dimethylaminopyridine were dissolved in 10 ml of methylene chloride, and diketene was added while cooling the solution with ice. After stirring the solution for 30 minutes under cooling with ice, water was added and the solution was extracted with methylene chloride. The resulting extract was concentrated under reduced pressure to give 4.7 g of an oily product (yield: 97%). The IR and NMR data of the compound thus obtained are as follows: ##STR59##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[C:4]([OH:9])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Cl)c(Cl)cc1O
Temperature: 20 °C
Reaction time: 8 h
Yield: 1029.6 %

Procedure:
A solution of 3,4-dichlorophenol [AK Scientific] (30 g, 18 mmol) in acetyl chloride (19 mL, 270 mmol) was stirred at 60° C. for 2 hours. The reaction mixture was cooled to 20° C., treated with aluminum trichloride (37 g, 280 mmol) portionwise, and heated at 180° C. for 30 minutes. The reaction mixture was cooled to 20° C. and the solution hardened into a solid block that was not easy to break apart. This material was cooled to 0° C. and quenched slowly with 1 M HCl in portions. The solid block of material slowly broke apart with enough HCl and this heterogenous mixture was stirred at 20° C. overnight to ensure uniformity. The solid was filtered, washed with copious amounts of water, and dried under vacuum to give the desired product (38 g, quantitative) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH2:20][CH3:21])[N:4]([CH2:23][CH2:24][CH3:25])[N:3]=1.[OH-].[Na+]>O.C(O)C>[CH3:1][C:2]1[C:6]2[C:7](=[O:8])[NH:9][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:10][C:5]=2[N:4]([CH2:23][CH2:24][CH3:25])[N:3]=1
Reactant: CCCOc1ccccc1C(=O)Nc1c(C(N)=O)c(C)nn1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from 3-methyl-5-(2-n-propoxybenzamido)-1-n-propylpyrazole-4-carboxamide (Preparation 7; 5.456 g, 0.0016 mol) and sodium hydroxide (3.16 g, 0.079 mol) in a mixture of water (150 ml) and ethanol (30 ml), by the method of Example 13, and was obtained as a white solid (4.863 g, 94%) after column chromatography. A sample crystallised from ethyl acetate-hexane as colourless needles, m.p. 112-114° C. Found: C,66.35; H,6.79; N,17.12. C18H22N4O2 requires C,66.24; H,6.79; N,17.17%.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:6][C@H:5]2[CH2:26][C@@H:3]1[C:4]2([CH3:28])[CH3:27].C(N(CC)CC)C.[C:36]1([CH2:42][CH2:43][C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:36]1([CH2:42][CH2:43][C:44]([N:8]([CH:9]2[CH2:10][CH2:11][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH2:13][CH2:14]2)[C@H:7]2[CH2:6][C@H:5]3[CH2:26][C@H:3]([C:4]3([CH3:28])[CH3:27])[C@@H:2]2[CH3:1])=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOC(=O)c1ccc(C2CCC(N[C@H]3C[C@H]4C[C@@H]([C@@H]3C)C4(C)C)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C2CCC(N(C(=O)CCc3ccccc3)[C@H]3C[C@H]4C[C@@H]([C@@H]3C)C4(C)C)CC2)cc1
Reaction time: 24 h

Procedure:
To a solution of EXAMPLE 45C (192 mg, 0.5 mmol), triethylamine (0.077 mL, 0.55 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) in tetrahydrofuran (5 mL) was added 3-phenylpropanoyl chloride (0.082 mL, 0.55 mmol), and the reaction was stirred for 24 hours. The residue was chromatographed on silica gel using 20-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8](=[CH:14][NH:15][C:16]([CH3:27])([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](Cl)[CH:3]=1>CS(C)=O.O>[Br:1][C:2]1[CH:29]=[C:28]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[C:16]([CH3:27])([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CNC(C)(C)CO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(Br)cc1Cl
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2c1=O
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
13bm) 4.3 g of ethyl 2-(4-bromo-2-chloro-benzoyl)-3-[2-(tert.-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethylamino]-acrylate (Example 13bl)) were dissolved in 40 ml of dimethyl sulphoxide under argon, treated with 1.1 g of potassium tert.-butylate and stirred for 15 min. Then, the mixture was stirred at 50° for 1.5 hrs. After cooling the mixture was diluted with 200 ml of water and the product was then extracted with two 200 ml portions of ethyl acetate, purified by silica gel chromatography in hexane/ethyl acetate 1:1 and crystallized from 30 ml of hexane/ethyl acetate 1:1. 2.45 g (62%) of ethyl 7-bromo-1-[2-(tert.-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylate were obtained as white crystals. M.p. 133° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: COC(CN)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(CNCc1ccc(-n2ccnc2)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2,2-dimethoxyethylamine (526 mg) and 4-(1H-imidazol-1-yl)benzaldehyde (861 mg) in methanol (25 ml) was added acetic acid (600 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, sodium triacetoxyborohydride (1.59 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and to the residue was added 1 N sodium hydroxide solution. The mixture was extracted with dichloromethane, dried and concentrated to give colorless oil of the title compound (1.21 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:20][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Product: COc1cccc(Nc2cc(O)ccc2[N+](=O)[O-])c1
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
4 g of 3-fluoro-4-nitrophenol and 9.4 g of m-anisidine were mixed and stirred for 2.5 hours at 150° C. After cooling, it was dissolved in dichloromethane and extracted three times with 1N aqueous hydrochloric acid. The organic phase was dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.