Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[C:42]([CH3:43])[C:35]=12.C(#N)C>C(Cl)Cl>[Cl:33][C:34]1[C:35]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Cc1cnc2[nH]cnc(Cl)c1-2
Agent: Br
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 62 (1.06 g, 2.1 mmol) in CH2Cl2 (30 mL) was added HBr (5.7 M in acetic acid; 2.2 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×15 mL). The resulting oil was dissolved in MeCN (10 mL) and added dropwise into a solution of the sodium salt of 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see J. Med. Chem. 33: 1984 (1990)] (0.62 g, 3.7 mmol) in anhydrous acetonitrile (70 mL), and NaH (60% in mineral oil, 148 mg, 3.7 mmol), after 2 h of vigorous stirring at rt]. The combined mixture was stirred at rt for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (250+100 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×5 cm) using hexane/ethyl acetate (9/1, 5/1, 3/1) gradient as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.87 g) as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Solvent: O
Product: O=C(c1ccccc1)c1ccc(F)c(Cl)c1

Procedure:
3-chloro-4-fluorobenzoyl chloride (1.0 g), benzene (2 ml) and ferric chloride (0.28 g) were heated to reflux for 16 h then diluted with water, extracted with ethyl acetate and the organics dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound as a brown solid (0.8 g).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=1.O1CCCC1.O.[OH-].[Li+]>O>[F:13][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(C(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(F)F)n1
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of methyl 6-(difluoromethyl)pyridine-2-carboxylate (0.58 g, 3.1 mmol, from Step 1) in Water (22 mL) and Tetrahydrofuran (20 mL, 250 mmol) was added Lithium hydroxide, monohydrate (0.65 g, 15 mmol). The reaction was stirred for 2 hours. The basic mixture was extracted with ether, which was discarded. The mixture was then acidified by the addition of 1N HCl and the volume of solvent reduced in vacuo. The product was purified via preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.1% TFA). The eluent containing the desired mass was evaporated by rotary evaporation to afford a solid product (0.35 g, 65%). 1H NMR (400 MHz, CD3OD): δ 8.27 (ddd, 1H), 8.17 (dd, 1H), 7.92 (dd, 1H), 6.78 (t, 1H); 1H NMR (400 MHz, CD3OD): δ−117.52 (d, 2F); LCMS (M+H)+: 173.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:17])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
3-methoxy-4-nitrobenzoic acid (Aldrich; 9 g, 45.65 mmol) was suspended in toluene (90 mL) and thionyl chloride (9.99 mL, 136.95 mmol) added and the mixture heated to reflux for 1 hour. The reaction was evaporated to yield the title compound as a brown solid (9.84 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:39]=1[C:40](Cl)=[O:41]>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:40]([C:39]2[C:38]([Cl:37])=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:47])=[O:41])=[CH:24][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCNC(C)=O)CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCNC(C)=O)CCCC1
Yield: 106.7 %

Procedure:
To a solution of 4-amino-N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (195 mg, 0.498 mmol) and diisopropylethylamine (0.0950 mL, 0.548 mmol) in dichloromethane (1 mL) was added a solution of 2,6-dichlorobenzoyl chloride (110 mg, 0.523 mmol) in dichloromethane (1 mL). The resultant mixture was stirred overnight then was concentrated in vacuo and transferred to a separatory funnel containing ethyl acetate (50 mL) and water (10 mL). The separated aqueous layer back-extracted with ethyl acetate (1×25 mL). The combined organic layer was washed in turn sat. solution of Na2CO3 and brine, then was dried over MgSO4, filtered and concentrated in vacuo to provide crude N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (300 mg).
Reaction SMILES: [CH2:1](OS(OCC)(=O)=O)[CH3:2].[CH3:10][N:11]([CH3:30])[S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13].[ClH:31]>[OH-].[Na+]>[ClH:31].[CH2:1]([N:27]1[CH2:26][CH2:25][N:24]([C:23]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[S:12](=[O:13])(=[O:14])[N:11]([CH3:30])[CH3:10])[CH2:29][CH2:28]1)[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)ccc1N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N(C)C)CC1

Procedure:
16 Grams of diethylsulfate were added dropwise, at room temperature, while being mixed in a vibro-mixer, to a solution of 31.5 g of 3-dimethylsulfamoyl-4-(piperazine-1-yl)-benzoic acid (0.1 mole), which had been prepared according to Example 15, in 0.3 l of 1N NaOH. The mixture was allowed to react for another 3 hours while being mixed in the vibro-mixer. Subsequently the solution was acidified with 5N HCl, and the separated hydrochloride was recrystallized from ethanol and water.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(C)cc1Br
Temperature: 65 °C
Reaction time: 32 h

Procedure:
To a solution of 3-bromo-2-chloro-5-methylpyridine [17282-03-0] (5 g, 24.2 mmol) in MeOH (80 mL) was added a solution of sodium methoxide (5.4M in MeOH) (25 mL, 135 mmol) and the mixture was stirred at 65° C. for 32 h. The resulting suspension was filtered and the mother liquor was concentrated. Et2O and H2O were added and the phases were separated. The organic layer was washed with H2O and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (heptane/EtOAc: 90:10→0:100) to afford the title compound. tR: 1.03 min (LC-MS 1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([C:26]([F:29])([F:27])[F:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)-methoxy)benzoate (3.70 g, 8.88 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was triturated in hexanes (10 mL), the solid was filtered and dried to give the title compound (2.20 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.1 Hz, 1H), 6.59 (d, J=12.3 Hz, 1H), 4.11 (s, 2H), 2.03-1.88 (m, 3H), 1.76-1.60 (m, 5H), 1.50-1.21 (m, 3H), 0.94-0.83 (m, 2H), 0.64-0.55 (m, 2H); MS (ES+) m/z 361.1 (M+1).
Reaction SMILES: C1COCC1.[C:6]([C:10]1[C:15]([F:16])=[CH:14][C:13]([CH:17]2[CH2:19][CH:18]2[C:20]([O:22]CC)=[O:21])=[CH:12][C:11]=1[F:25])([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>CO>[C:6]([C:10]1[C:11]([F:25])=[CH:12][C:13]([CH:17]2[CH2:19][CH:18]2[C:20]([OH:22])=[O:21])=[CH:14][C:15]=1[F:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C1CC1c1cc(F)c(C(C)(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1c(F)cc(C2CC2C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a toluene (50 ml) solution of the compound of Example 38C (4.0 g, 20.4 mmol), Co(TPP) (411 mg, 0.61 mmol) and 1-methyl-1H-imidazole (5.0 g, 61.2 mmol), ethyl diazoacetate (3.5 g, 30.6 mmol) was added and the mixture was stirred for 5 minutes at room temperature followed by additional stirring for 2 hours at 80° C. Then, evaporation and purification by silica gel column chromatography, eluting with gradually from hexane to hexane/EtOAc (20:1), gave ethyl 2-(4-tert-butyl-3,5-difluorophenyl)cyclopropanecarboxylate (4.4 g, 76%, trans). To a THF (5 ml) solution of ethyl 2-(4-tert-butyl-3,5-difluorophenyl)cyclopropanecarboxylate (4.4 g, 15.5 mmol), 2M sodium hydroxide aqueous solution (30 ml) and MeOH (30 ml) were added and the mixture was stirred for 1 hour at room temperature. After the reaction was completed, the aqueous layer was extracted, and then acidified with 2M HCl aqueous solution and the whole was extracted with EtOAc, followed by evaporation, to give the title compound (3.48 g, 88%) as white solids.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[O-:33][N+:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[N:1]([CH2:14][CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH:2]=[N:3][C:4]=2[CH:5]=1
Reactant: O=C(CCCn1cnc2cnc3ccccc3c21)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(CCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one (4.08 g, 12.9 mmol) by reaction with m-CPBA (3.20 g, 14.2 mmol) to provide 4-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one followed by reaction with p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) and ammonium hydroxide solution (22 mL) to provide 4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one) as white needles, mp 209-211° C.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C[Si]([C:21]#[CH:22])(C)C>CN(C=O)C.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>[C:21]([C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1)#[CH:22]
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc(OC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, the mixture of the product from Example 1A (800 mg, 2.4 mmol), trimethylsilylacetylene (Aldrich, 392 mg, 4 mmol), Pd(PPh3)4 (Aldrich, 29 mg, 0.025 mmol) and Cul (Strem Chemicals, 10 mg, 0.05 mmol) in DMF (10 mL) was stirred at ambient temperature overnight. DMF then was removed under reduced pressure. The residue was treated with tetrabutyl ammonium fluoride (Aldrich, in THF, 1 M, 5 mL) at room temperature for 3 h. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3 H2O, 90:10:1, Rf. 0.30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) δ 1.42-1.54 (m, 1H), 1.61-1.87 (m, 2H), 1.93-2.07 (m, 1H), 2.10-2.18 (m, 1H), 2.71-3.00 (m, 5H), 3.19-3.37 (m, 2H), 4.49-4.56 (m, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H) ppm. MS (DCI/NH3): m/z 228 (M+H)+.
Reaction SMILES: [CH2:1]([C:7](C)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:10](=[O:17])([O:14][CH2:15][CH3:16])OCC.[H-].[Na+]>O1CCOCC1>[CH2:1]([C:7](=[O:8])[C:10]([O:14][CH2:15][CH3:16])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC(C)=O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCC(=O)C(=O)OCC
Yield: 62.5 %

Procedure:
A solution of 20.0 g of methyl hexyl ketone in 100 ml of dioxane was dropped into a solution comprising 210 ml of diethyl carbonate, 12.8 g of sodium hydride dispersed in oil at a concentration of 60% by weight and 100 ml of dioxane in an argon atmosphere, and the mixture was refluxed overnight. Then, the solvent was removed and the residue was distilled under a reduced pressure to obtain 20.0 g of ethyl hexylketoacetate having a boiling point of 83° C. under 0.65 mmHg. The yield was 62.5%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)OCCO2

Procedure:
To a well-stirred and ice-cooled solution of 1,4-dioxa-8-azaspiro[4.5]decane (34.9 mmol, 5 g) in dichloromethane (200 mL) under an argon atmosphere, was added triethylamine (52.4 mmol, 7.3 mL) and then benzyloxycarbonyl chloride (42 mmol, 5.93 mL) dropwise. The suspension was stirred at room temperature for 24 hours and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give an oily residue which was chromatographed on silica gel eluting with a mixture of ethyl ether and petroleum ether to afford 8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro [4,5] decane in quantitative yield. 1H-NMR (CDCl3): 1.63 (m, 4H); 3.56 (m,4H); 3.89 (s, 4H); 5.09 (s, 2H); 7.28 (s, 5H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([C:14]2([CH3:15])[O:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1
Reactant: CC(=O)c1cccc(-c2ccncc2)c1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2cccc(-c3ccncc3)c2F)OCCO1
Yield: 64.8 %

Procedure:
A mixture of 1-(2-fluoro-3-pyridin-4-ylphenyl)ethanone (1.28 g, 5.95 mmol), ethylene glycol (1.66 ml, 29.75 mmol), molecular sieves (5 g, 3 Å) and p-toluenesulfonic acid monohydrate (0.11 g, 0.59 mmol) in toluene (20 ml) was heated at reflux for 2 h. The molecular sieves was filtered off and the residue was evaporated to dryness. Purification by flash column chromatography (ethyl acetate) gave the title compound (1.0 g). MS m/z (rel. intensity, 70 eV) 259 (M+, 1), 245 (15), 244 (bp), 200 (56), 87 (17).
Reaction SMILES: C[O:2][C:3]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26]C)=[C:18]([CH3:28])[C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1.C(#N)C.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:25][O:24][C:20]1[C:19](=[O:26])[C:18]([CH3:28])=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:21]=1[O:22][CH3:23]
Reactant: COc1c(C)c(Cc2ccc(CCCC(=O)O)cc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Yield: 64.2 %

Procedure:
The compound (260 mg, 0.67 mmol) obtained in Step 2, acetonitrile (5 ml), water (1.6 ml), and CAN (920 mg, 1.70 mmol) were used, and a method similar to that described in Step 3 of Example 21 was employed and then the reaction mixture was purified by a silica gel column chromatography (methylene chloride:methanol=9:1) to yield the title compound (154 mg, 0.43 mmol, yield 74%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C1C=CC=CC=1>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:21]([O:22][CH2:23][CH3:24])=[O:25])[CH2:13][CH2:12]1)=[O:15]
Reactant: O=C(c1cccs1)C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(C(=O)c2cccs2)CC1
Reaction time: 6 h

Procedure:
To a stirred mixture of 15 parts of [1-(phenylmethyl)-4-piperidinyl](2-thienyl)methanone in 120 parts of benzene are added dropwise 8 parts of ethyl carbonochloridate. Upon completion, the whole is heated to reflux and stirred for 6 hours at reflux temperature. The reaction mixture is cooled, filtered and evaporated, yielding 13 parts of ethyl 4-(2-thienylcarbonyl)-1-piperidinecarboxylate as a residue.
Reaction SMILES: CC(O)([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:12][C:8]1[CH:7]=[C:6]([C:5]#[CH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(O)C#Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cccc(N)c1
Yield: 104.7 %

Procedure:
2 grams of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol were dissolved in 15 ml of toluene containing one pellet (0.1 gram) of sodium hydroxide which had been crushed to a powder. The mixture was charged to a 100 ml, round-bottom flask equipped with a Dean-Stark trap and condenser. The mixture was refluxed for one hour, and the acetone byproduct was removed periodically through the Dean-Stark trap. The reaction product was then cooled, and the mixture filtered to remove particles of caustic. After the solvent was stripped, a quantitative yield of 3-aminophenylacetylene (1.4 grams) of greater than 98% purity as analyzed by gas chromatography was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])[CH3:2].C(N(CC)CC)C.Cl.[NH2:37][OH:38]>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:37][OH:38])=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCC)c1F
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
The (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester (136 mg) described in example 2.2 was dissolved in ethanol. Triethylamine (712 mg) and hydroxylamine hydrochloride (245 mg) were added and the mixture was stirred for 18 h at room temperature. The mixture was concentrated; the residue was dissolved in CH2Cl2 and washed with water. The product was purified by column chromatography (CH2Cl2/MeOH) to give 87 mg of (RS)-(3,5-diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester as a colorless foam. MS: 420 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14].[OH-].[Na+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCOC(C)=NO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(C)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 17 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4-Chloronitrobenzene, 136.2 g, and 111.4 g ethyl N-hydroxyacetimidate are dissolved in 216 ml DMF. The temperature is adjusted to 30° C. and 41.6 g solid NaOH is added in 8 portions keeping the temperature at 30-35° C. After one hour the temperature is adjusted to 40-45° C. and the mixture stirred for 1.5 hours. Cooling is applied and 520 ml water is fed at such a rate as to keep the temperature at ca 40° C. The slurry formed is cooled to 17° C. and filtered. The filter cake is washed with 175 ml ethanol/water 90/10 (V/V) followed by 175 ml water. Wet product, 214.5 g, corresponding to 192 g dry ethyl N-(4-nitrophenoxy)acetimidate is isolated. Yield 98.5%.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:29]=[CH:28][C:6]2[O:7][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:27]=[CH:26][C:20]4[CH:21]=[CH:22][C:23](=[O:25])[O:24][C:19]=4[CH:18]=3)[CH2:9][O:10][C:5]=2[CH:4]=1.[C:30](Cl)(=[O:32])[CH3:31]>C(O)(=O)C>[C:30]([O:2][C:3]1[CH:29]=[CH:28][C:6]2[O:7][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:27]=[CH:26][C:20]4[CH:21]=[CH:22][C:23](=[O:25])[O:24][C:19]=4[CH:18]=3)[CH2:9][O:10][C:5]=2[CH:4]=1)(=[O:32])[CH3:31]
Reactant: O=c1ccc2ccc(OCCCNCC3COc4cc(O)ccc4O3)cc2o1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2c(c1)OCC(CNCCCOc1ccc3ccc(=O)oc3c1)O2
Reaction time: 8 h

Procedure:
7-[3-[[(2,3-Dihydro-6-hydroxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.10 g, 0.24 mmole), prepared as in example 5 above, was dissolved in 50 ml of glacial acetic acid and 3.05 ml (43 mmole) of acetyl chloride added in portions over a 30 minute period, during which the reaction mixture was gently warmed with a heat gun. The solvent and excess reagent were then removed in vacuum and diethyl ether added. Upon standing overnight, 0.030 g of the title compound as a monohydrochloride, m.p. 175° C., crystallized.