Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[C:20]([OH:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[C:17]([F:16])([F:27])[F:28])[C:12]#[N:13])=[CH:14][CH:15]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(C#N)=C(O)c2ccccc2C(F)(F)F)cc1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture comprising 5.8 g of 63% sodium hydride and 137 ml of tetrahydrofuran was heated, and a mixture comprising 13.5 g of 4-tert-butylbenzyl cyanide, 15.0 g of 2-trifluoromethylbenzoyl chloride and 50 ml of tetrahydrofuran, was dropwise added thereto over a period of 2 hours under reflux. After completion of the dropwise addition, the reaction was carried out at the same temperature for 2 hours. Tetrahydrofuran in the reaction mixture was distilled off, and 250 ml of water was poured into the residue. Then, 80 ml of n-hexane was added thereto, and the mixture was stirred and washed for 10 minutes and then left to stand for 30 minutes. Then, the aqueous layer was separated. To the aqueous layer, 8.3 g of concentrated hydrochloric acid was gradually dropwise added with stirring, followed by further stirring for 30 minutes. Precipitated crystals were collected by filtration and washed with 100 ml of water and then dried at 55° C. for 24 hours to obtain 23.7 g of the desired product. The NMR spectrum data of this product were as follows.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].Br[CH:20](Br)[CH3:21]>O1CCCC1>[CH:1]1[C:13]2[CH:12]([CH2:17][CH2:16][CH:15]3[C:14]4[CH:21]=[CH:20][CH:8]=[CH:7][C:6]=4[C:5]4[C:4]3=[CH:3][CH:2]=[CH:1][CH:13]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)Br
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)-c1ccccc1C2CCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 70 %

Procedure:
About 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After one hour, 2.3 ml (0.25 m) of dibromoethane in 25 ml of tetrahydrofuran was added. The solution was stirred for 3 hours. The yellow solution was washed with 50 ml of an aqueous NH4Cl solution (5 g NH4Cl/50 ml H2O), then washed with 50 ml of water and then the organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The light yellow residue was washed twice with 25 ml of pentane. The resulting product was white. The yield was 12.5 g, i.e. a yield of about 70%, based on the moles of fluorene reacted. The product was confirmed through 1H NMR, 13C NMR, mass spectroscopy, and gas chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH2:32])([CH3:31])[CH3:30]>>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH:32][C:14]([C:12]1[CH:11]=[CH:10][C:9]([N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:15])([CH3:31])[CH3:30]
Reactant: COCCOCC(C)(C)N
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Product: COCCOCC(C)(C)NC(=O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140 a) and 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethylamine (CAN 947723-29-7) as starting materials, MS (EI): m/e=454.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][C@H:14]([C:25]([OH:27])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][C@@H:14]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(3R,5S)-5-{[(Benzyloxy)carbonyl]amino}-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (49.2 g), morpholine (11.4 ml), 1H-benzotriazol-1-ol (10.0 g) and triethylamine (40 ml) were dissolved in DMF (250 ml), WSC.HCl (30.0 g) was added and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (62.9 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2].CCO.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([OH:33])[C@H:29]([NH2:32])[CH2:30][OH:31])=[CH:24][CH:23]=1)([O-:21])=[O:20].Cl>CO.O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([OH:33])[C@H:29]([NH2:32])[CH2:30][OH:31])=[CH:26][CH:27]=1)([O-:21])=[O:20].[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(=O)O
Agent: Cl
Agent: N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 76 °C

Procedure:
200 g N-acetyl-indoline-2-carboxylic acid (purity 96.5%) was dissolved in 1760 ml of a mixture containing 90% EtOH, 5% water and 5% MeOH, with heating to 76° C., and with mechanical stirring. 138 g/0.69 eq (1R,2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol (99.5% chemically pure, [a]20 D =-28.5° (c=0.4, 1N HCl)) was dosed in portions in 30 min. at 73-76° C. After cooling to 70° C., grafting with 1 g S-salt took place, followed by cooling to 15° C. in 3 hours and 30 minutes' subsequent stirring. After filtration over a P4 glass filter, 3 washings with 200 ml EtOH took place. After air-drying, 158.1 g yellow (S)-N-acetyl-indoline-2-carboxylic acid-(1R,2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol salt was obtained, corresponding to a yield of 40.3%. Enantiomeric excess=99.0% (chiral HPLC).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:16][CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.C(OCC)C.[ClH:40]>CO>[ClH:40].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N(CCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(O)C[C@H](Cc1c[nH]c2ccccc12)NCCNCCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Combine 2-[(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino]-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine (4.77 g, 10 mmol) and diethyl ether (50 mL). Cool to 0° C. in an ice-bath. Slowly pass hydrogen chloride gas through the solution for 30 minutes. Stir for 4 hour at 0° C. Warm to ambient temperature and stir for 1 hour. Evaporate in vacuo to give a residue. Dissolve the residue in methanol and triturate the residue with diethyl ether to form a solid. Filter and dry under vacuum to give the title compound. Elem. Anal. calculated for C22H27N3 O2 . 0.50 H2O: C, 59.06; H, 6.76; N, 9.39. Found: C, 58.90; H, 7.01; N, 9.18.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:31]([F:34])([F:33])[F:32])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH:28]([F:30])[F:29])[CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>O.C(OCC)(=O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:7]=[C:6]([Cl:5])[CH:11]=[C:10]([Cl:12])[CH:9]=3)([C:31]([F:33])([F:34])[F:32])[O:17][N:16]=2)=[CH:19][C:20]=1[O:27][CH:28]([F:29])[F:30]
Reactant: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Yield: 90.8 %

Procedure:
In a mixture of 5.0 mL of water, 1.0 mL of acetic acid and 1.22 g of reduced iron, a solution of 2.0 g of 5-(3,5-dichlorophenyl)-3-(3-difluoromethoxy-4-nitrophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 15 mL of ethyl acetate was added dropwise at 75° C. under stirring with heating. After the completion of the addition dropwise, it was stirred at the same temperature for 2.5 hours. After the completion of the reaction, the reaction mixture was subjected to hot filtration through Celite, 20 ml of water was added in the filtrate, extracted with ethyl acetate (20 ml×2). The combined organic phases were washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.7 g of the crude aimed product as yellow resinous substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[C:42]([O:45][CH2:46][CH3:47])(=[O:44])[CH3:43]>C1COCC1>[C:42]([O:45][CH2:46][CH3:47])(=[O:44])[CH3:43].[CH2:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C1CCCCC1

Procedure:
The amine AM17 (1 eq.) was initially introduced into the flask together with the corresponding acid (1 eq.) under nitrogen. TBTU (1 eq.) and HOBT (1 eq.) were then added and the solids were dissolved in THF (8.5 ml/mmol of amine). N-ethyldiisopropylamine (2 eq.) was added to this mixture with constant stirring and the mixture was subsequently stirred at room temperature overnight. Ethyl acetate was added to the reaction solution and the mixture was washed with sat. NaCl solution, NaHCO3 solution, NaCl and with NH4HSO3 solution and evaporated to dryness with nitrogen and the residue was dried overnight using an oil pump. It was possible to obtain the desired product by means of flash column chromatography (mobile phase: ethyl acetate/cyclohexane, 1:5).
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][OH:22])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].[N:28]#[C:29]Br.[OH-].[Na+]>CO>[NH2:28][C:29]1[O:22][CH2:21][C@H:2]([CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[N:1]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1=N[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a stirred suspension of N-[4-((S)-3-Amino-4-hydroxy-butyl)-phenyl]-4-chloro-benzamide (250 mg) and sodium acetate (124 mg) in methanol (10 ml) was added dropwise a solution of cyanogen bromide (100 mg) in methanol (3 ml). The resulting pale yellow solution was then stirred at room temperature for 16 h. The reaction mixture was poured into 1 N aq. NaOH and extracted twice with dichloromethane/THF. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; eluant: 0% to 100% EtOAc in heptane, then 0% to 30% MeOH in EtOAc) to afford N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide (150 mg, 56%) as a white solid. MS (ISP): 346.1 ([{37Cl}M+H]+), 344.2 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl.C(N(CC)CC)C>C(O)(C)C>[C:1]([N:5]1[CH2:9][CH:8]([OH:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: ClCC1CO1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)N1CC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of tert-butylamine (10 mmol) in isopropylalcohol (20 mL) was added dropwise epichlorohydrine (10 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was re-dissolved in acetonitrile (20 mL) and triethylamine (20 mmol) was added. The mixture was heated at 100° C. for 24 h, cooled to rt and filtered. The filtrate was concentrated providing 1-tert-butyl-azetidin-3-ol (1.1 g). MS (ESI): mass calcd. for C7H15NO, 129.1; m/z found, 130.1 [M+H]+. 1H NMR (CDCl3): 6.15-5.70 (br s, 1H), 4.84-4.72 (m, 1H), 4.24-4.12 (m, 2H), 4.03-3.87 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH:1]([C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[O:9][Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([N:7]1[C@H:4]([CH:1]([CH3:2])[CH3:3])[C@H:5]([O:9][Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[C:6]1=[O:8])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H]1C(=O)N[C@@H]1C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)O[C@@H]1C(=O)N(C(=O)c2ccccc2)[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of (±)-cis-4-isopropyl-3-triethylsilyloxy-azetidin-2-one (486 mg, 2.00 mmole), benzoyl chloride (0.255 mL, 1.1 equiv), diisopropylethyl amine (0.346 mL, 1.2 equiv) and p-dimethylaminopyridine (244 mg, 1 equiv) in dry DCM (6 mL) was left stirring at 0° C. for 6 hr. The bath was removed and the reaction was left stirring overnight. It was then diluted with DCM and washed with water, aq. HCl solution (0.1 N), saturated aq. NaHCO3 solution, brine and dried (Na2SO4). Removal of the solvent followed by silica gel column chromatography (gradient elution with 0 to 5% EtOAc in hexane) gave the title compound: 1H NMR δ (CDCl3) 0.47-0.94 (m, 21H), 2.09 (m, 1H), 4.07 (m, 1H), 4.75 (m, 1H), 7.24-7.76 (m, 5H).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[CH3:16]N(C)C=O.[H-].[Na+].CCC[CH2:26][CH2:27][CH3:28]>>[CH3:16][C:27](=[CH2:26])[CH2:28][N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11]
Reactant: CN(C)C=O
Reactant: CCCCCC
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [Na+]
Product: C=C(C)CN1C(=O)c2cscc2Nc2ccccc21
Reaction time: 2 h

Procedure:
An 11.8 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 175 ml. of dimethylformamide is stirred. A 2.8 g. portion of 50% sodium hydride in mineral oil is treated with hexane to remove the mineral oil and then added to the reaction mixture. After 2 hours of stirring, 6.7 g. (7.2 ml.) of methallyl chloride is added. The mixture is stirred overnight and poured into ice-water. The mixture is extracted with four 250 ml. portions of methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate, filtered and concentrated to dryness. The crude product is dissolved in 10 ml. of 40% methylene chloride in hexane and chromatographed on an alumina column, eluting with the same solvent. Those fractions which contain the desired product as determined by thin layer chromatography are combined and concentrated to give the crude product. This product is heated to solution in 25 ml. of benzene, filtered and the solid which forms is collected, washed with hexane and dried giving the desired product, mp. 161°-163° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][CH:26]=1>ClCCl.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][CH:26]=1)=[O:8]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(O)c1ccco1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccco2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of dichloromethane was dissolved 0.56 g (5 m-mol) of 2-furancarboxylic acid. To this solution was added 0.7 ml of triethylamine, and the mixture was cooled to -20° C. Next, 0.65 ml of isobutyl chloroformate was added to the mixture and the whole was stirred for 30 minutes at a temperature from -10° C. to -20° C. To this mixture was added a dimethylformamide solution containing 1.0 g (4.9 m-mol) of 6-(p-aminophenyl)-5-methyl-4,5-dihydropyridazinone. After removing the ice bath, the mixture was stirred for 3 hours at room temperature and the solvent was then distilled off under reduced pressure. Water was added to the residue and a solid material was collected by filtration. The solid material was washed with water and dichloromethane and then recrystallized from methanol-water whereby 570 mg of the title compound was obtained. M.P. 213°-216° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([CH2:12][C:13]([O:15]CC)=[O:14])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:21]O.CO.C([O-])(=O)C>O>[CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]2[CH2:12][C:13](=[O:14])[O:15][N:21]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C2=NOC(=O)C2)cc1

Procedure:
To a mixture 23.0 g of ethyl 4-methanesulfonamidobenzoylacetate, 5.8 g of hydroxylamine hydrochloride, and 35 ml of methanol, 8.2 g of pottasium acetate was added, and the mixture was refluxed for 30 minutes while being heated. The reaction mixture was poured into 210 ml of water, and the precipitated crystals were collected by filtering and dried, thereby obtaining 1.39 of 3-(4-methanesulfonamidophenyl)isoxazolin-5-one.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=O)[N:4]([CH3:6])[CH3:5].C(Cl)(=O)C([Cl:12])=O>ClCCCl>[Cl-:12].[CH3:1][N:2]([CH3:8])[C:3]([Cl:12])=[N+:4]([CH3:6])[CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C(=O)N(C)C
Solvent: ClCCCl
Product: CN(C)C(Cl)=[N+](C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
49.4 g of tetramethylurea were dissolved in 400 ml of 1,2-dichloroethane and 30.0 g of oxalyl chloride were added dropwise to the solution at room temperature over a period of 15 minutes. The resulting solution was stirred at room temperature for 15 minutes and further stirred in an oil bath at 65° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to 200 ml and allowed to cool, upon which crystals separated out. The crystals were obtained by filtration, washed with ether and dried under reduced pressure to obtain 30.0 g of a white, hygroscopic intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[N:24]1[CH2:23][CH2:22][N:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Clc1ncnc2ccc(Br)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(N2CCN(c3ncnc4ccc(Br)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
A mixture of 300 mg 6-bromo-4-chloroquinazoline, 350 mg 1-[3-(trifluoromethyl)phenyl]piperazine, 0.18 mL triethylamine and 5 mL N,N-dimethylformamide was stirred at room temperature for 4 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a yellow oil. This product was crystallized from diethyl ether to give 360 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[OH:17])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:17][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CN1C2CCC1C(O)C(c1ccc(Cl)cc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(Cl)cc1)C2
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A solution of 1.08 g (4.3 mmol) of (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-2-ol [J. Org. Chem. 35, 802, 1970)] in 5 ml of tetrahydrofuran was added dropwise to a suspension of 0.206 g (4.3 mmol) of sodium hydride (50% dispersion in refined oil) in 6 ml of tetrahydrofuran and the mixture was stirred at 50° C. for 60 minutes. Subsequently, the mixture was cooled to room temperature and treated with 0.95 g (4.3 mmol) of 2-bromomethylnaphthalene in 5 ml of tetrahydrofuran. After 2 hours at 50° C. the reaction solution was poured into 60 ml of ice-water and extracted three times with 25 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent and yielded 1.04 g (62% of theory) of (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-8-methyl-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane as a light yellow oil, Rf : 0.43 (silica gel, methylene chloride;methanol=95:5), MS: 392 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:25](=[O:27])[CH3:26])[CH:8]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C2Nc3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(C2N(C(C)=O)c3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Yield: 99 %

Procedure:
1-Nitro-5-(p-methoxyphenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is reacted with acetic anhydride as described in Example 27 to give 1-nitro-5-(p-methoxyphenyl)-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline with a yield of 99%. M.p.: 153°-154° C.