Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Sodium hydride (60%, 0.12 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro 4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.00 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C., which is stirred for 15 minutes. To the reaction solution is added dropwise a solution of 2-chloro-5-trifluoromethyl pyridine (0.60 g) in 1,2-dimethoxyethane (20 ml) at -5° C., which is stirred for 15 minutes. The reaction mixture is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.80 g of desired compound (refractive index: 1.5879).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([CH3:18])=[C:16]([NH2:19])[S:15][N:14]=2)=[CH:9][CH:8]=1>ClCCl>[NH2:19][C:16]1[S:15][N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=2)[C:17]=1[CH3:18]
Reactant: COc1ccc(-c2nsc(N)c2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(-c2ccc(O)cc2)nsc1N
Temperature: 25 °C
Yield: 106.8 %

Procedure:
Add boron tribromide (0.227 g, 0.909 mmol) to a solution of 3-(4-methoxy-phenyl)-4-methylisothiazol-5-ylamine (0.100 g, 0.455 mmol) in dichloromethane (5 mL) at −20° C. Stir and allow to warm to room temperature. Stir 4 h and quench with 1 N HCl. Extract with EtOAc (2 times 50 mL). Dry (MgSO4) and evaporate. The product is used for the next step without further purification. Yield: 106.8% ES-MS: m/e 207.0 (m+1).
Reaction SMILES: ClC1C=CC(C[N:7]2[C:15]3[C:10](=[CH:11][C:12](F)=[CH:13][CH:14]=3)[C:9](SC)=[C:8]2CC(OCC)=O)=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].CI.S(=O)(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CCOCC.O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CCOC(=O)Cc1c(SC)c2cc(F)ccc2n1Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: CCOCC
Product: c1ccc2[nH]ccc2c1
Reaction time: 2 h

Procedure:
To a cold (-78°), stirred solution of 560 mg of ethyl 1-(p-chlorobenzyl)-5-fluoro-3-methylthioindole-2-acetate from Example 3 in 6 75 mL dry tetrahydrofuran, under argon, was added 2.72 mL of a 0.63 M solution of potassium hexamethyldisilazide in toluene. After 2 h at -78°, 123 μL of methyl iodide was added and the mixture stirred at -78° for 30 min and 0° for 1 h. 10% aqueous sodium bisulfate and ether were then added. The organic layer was separated, washed with 10% aqueous sodium bisulfate, water and brine and dried over MgSO4. Filtration and concentration gave a pale yellow oil which was purified by flash chromatography on silica gel. Elution with a mixture of hexane ethyl acetate (85:15) gave an indole derivative, mp 131°-132°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28]C(OC(C)(C)C)=O)=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(N)cc2)cc1
Temperature: 60 °C

Procedure:
Trifluoroacetic acid (7.95 mL, 11.8 g, 102 mmol) was added over 5 minutes to a slurry of 4-{2-[4-(tert-butoxycarbonylamino)phenyl]ethoxy}phenyl methanesulfonate (17.6 g @ 95%, 40.8 mmol) in toluene (176 mL) at 20° C., and then heated to 60° C. to form a dark brown solution. A seed of pure product (0.05% by weight) was added and the reaction mixture heated at 60° C. for 17 hours during which period a dense solid crystallized. The reaction mixture was cooled to 20° C. and the solid isolated by filtration, washed by displacement with toluene (26 mL) and dried in a vacuum oven at 40° C. to yield the title compound as a dense, buff-coloured solid (16.1 g, 94%). HPLC (Rt 6.0 mins); m.p. 131-133° C.; 1H NMR (400 MHz, d6-DMSO) δ 7.35 (2H, d, J=8.4 Hz), 7.26 (2H, dt, J=10.8, 3.0 Hz), 7.13 (2H, d, 8.0 Hz), 7.05 (2H, dt, J=10.8, 3.0 Hz), 4.19 (2H, t, J=6.6 Hz), 3.31 (3H, s), 3.02 (2H, t, J=6.6 Hz), 2.9-4.7 (br); 13C NMR (100.6 MHz, d6-DMSO) δ 157.12, 142.46, 135.56, 133.65, 130.04, 123.31, 121.02, 115.45, 68.43, 36.92 and 34.14; MS (ES+) 308 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](=[N:6][OH:7])[NH2:5].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1.[H-].[Na+]>CN(C=O)C>[CH:16]1([CH2:19][O:7][N:6]=[C:4]([NH2:5])[C:3]2[C:8]([C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])[CH2:18][CH2:17]1
Reactant: NC(=NO)c1c(F)cccc1C(F)(F)F
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
In 100 ml of DMF was dissolved 26.6 g of 2-fluoro-6-trifluoromethylbenzamidoxime and 17.8 g of cyclopropylmethylbromide, and to the solution was added 4.8 g of sodium hydride (60% in oil) at 10° C. over 30 min. The solution was then stirred for 3 hours, and the solution reacted was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 24.8 g of the objective compound. m.p. 63-64° C.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].[NH2:13][C:14]1[C:15]([C:24](OC(C)=CC(=O)NC(C)(C)C)=[O:25])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>C1COCC1>[NH2:13][C:14]1[C:15]([C:24]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:25])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CSC(=N)N
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc2ccccc2nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSC(=N)NC(=O)c1nc2ccccc2nc1N

Procedure:
To NaOH (1 mol/l in water; 45.7 ml; 45.7 mmol) is added S-methylisothiourea sulphate (10.6 g; 38.1 mmol). The mixture is stirred until complete solution is achieved. The resulting solution is added to a suspension of 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3-aminoquinoxaline-2-carboxylate (example 4) (5.00 g; 15.2 mmol) in THF (80 ml). The mixture is stirred at r.t. for 3 h, then volatiles are evaporated. Ice-water (100 ml) is added. The precipitate formed is filtered off with suction, washed with water and then dried at 50° C. (C11H11N5OS).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][C@@H:14]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]2)[N:5]=[C:4]([NH:21][CH:22]=[O:23])[N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]=[O:23])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][C@@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1
Reactant: CC1(C)OC[C@@H](CONc2nc(NC=O)nc(Cl)c2NC=O)O1
Agent: CCOC(OCC)OC(C)=O
Product: CC1(C)OC[C@@H](COn2cnc3c(Cl)nc(NC=O)nc32)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
A solution of (S)-4-chloro-2,5-diformamido-6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamino)pyrimidine (2.1 g, 6.08 mmol) in diethoxymethyl acetate (30 ml) was stirred at 120° C. for 3 h. The reaction was evaporated to dryness, the residue dissolved in methanol (40 ml) and 0.88 ammonia (1 ml) and stirred for 1.5 h. at 25° C. Evaporation and chromatography of the residue on silica eluting with ethyl acetate-hexane 1:1 gave (S)-6-chloro-9-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-2-formamidopurine (1.3 g, 65%) as a white solid; m.p. 147°-8° C.; υmax (KBr) 3420, 3200, 1700, 1610, 1580, 1510, and 1440 cm-1 ; δH(CDCl3) 1.40(3H,S,CH3), 1.44(3H,S,CH3), 3.89(1H,m,CH2OCMe2), 4.16(1H,m,CH2OCMe2), 4.50(3H,m,CH+CH2ON), 8.23(1H,S,H- 8), 8.45(1H,br.d,J11.5 Hz,D2O exchangeable, NH) and 9.59(1H,d,J11.5 Hz,HCONH). Found C, 43.75; H, 4.29; N, 21.23%; M+ 327.0734; C12H14ClN5O4 requires C, 43.98; H, 4.31; N, 21.37%; M+ 327.0734.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br)([O-:33])=[O:32].P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(2-hydroxyethoxy)hexyl]-1,3-oxazolidin-2-one (0.20 g) in DMF (5 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.030 g) and the mixture stirred under nitrogen at 20° C. for 15 min. 3-nitrobenzylbromide (0.11 g) was added, and the mixture stirred at 20° C. for a further 3 h. Phosphate buffer (20 ml, pH6.5) was added and the mixture was stirred for 5 min before extracting with EtOAc (3×20 ml). The organic layer was washed with water (3×20 ml), dried over Na2SO4 and filtered. Solvent evaporation gave the crude product which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (7:3) followed by solvent evaporation in vacuo gave the title compound (0.10 g). LCMS RT=3.61 min, ES+ve 529(MH)+.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1>CO>[F:30][C:29]([F:32])([F:31])[C:25]1[N:26]=[C:27]([N:3]2[CH2:4][CH2:5][CH:6]([CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][C:11]3=[O:15])[CH2:7][CH2:8]2)[CH:28]=[CH:23][N:24]=1
Reactant: O=C1CCCN1CC1CCNCC1
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCCN1CC1CCN(c2ccnc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
Using the procedure described above in Examples 2 and 3, a mixture of 1-[(4-piperidinyl)methyl]-2-pyrrolidinone hydrochloride (II, 21.85 g, 0.1 mole) and sodium carbonate (26.5 g, 0.25 mole) in methanol (150 mL) was refluxed for one hour. The methanol was then removed in vacuo, and acetonitrile (150 mL) was added to the residue. The mixture was cooled and stirred as 4-chloro-2-(trifluoromethyl)pyrimidine (18.28 g, 0.2 mole) was added. The mixture was stirred at room temperature for 18 hours and then filtered and the filtrate concentrated in vacuo to give a thick residue which solidified upon being washed with hexane (100 mL). The light tan powder (23.8 g, 73%) which resulted was chromatographed (5% methanol/ethyl acetate on silica) to give 19.8 g as white crystals, m.p. 118.5°-120.5°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[C:10]([CH3:26])([CH3:25])[CH2:9]1)=O)(C)(C)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH3:25][C:10]1([CH3:26])[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)=[CH:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c(F)c3ccoc23)C(C)(C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CNCC=C1c1cc(F)c(F)c2ccoc12

Procedure:
A solution of 0.483 gm (1.34 mMol) 1-(tert-butoxycarbonyl)-3,3-dimethyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine in 5 mL previously deoxygenated 9:1 toluene:n-propanol was placed under vacuum and pressurized with nitrogen three times to exclude oxygen. To this solution were added 0.008 gm (0.036 mMol) palladium acetate and 0.024 gm (0.092 mMol) triphenylphosphine and the resulting mixture was stirred for 15 minutes. Then 0.28 gm (1.41 mMol) 4,5-difluorobenzofur-7-ylboronic acid, 0.085 gm (2.0 mMol) lithium chloride, and 0.74 mL (1.48 mMol) of previously deoxygenated 2.0 M aqueous sodium carbonate were added to the reaction mixture. The mixture was deoxygenated by subjecting it three times to a vacuum/nitrogen cycle, was heated to reflux for 4 hours, and was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between water and diethyl ether. The aqueous phase was extracted well with diethyl ether and all of the organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 20% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 0.374 gm (76.6%) 1-(tert-butoxycarbonyl)-3,3-dimethyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine as a crystalline white solid. A solution of 0.246 gm (0.68 mMol) 1-(tert-butoxycarbonyl)-3,3-dimethyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine in 3 mL 2 M hydrogen chloride in ethyl acetate was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to provide 0.202 gm of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=[CH2:12].CC(C)=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:8][C:7]([NH:9][C:19](=[O:20])[NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[N:6][C:4](=[O:5])[CH:3]=1
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Cc1cc(=O)nc(N)[nH]1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Yield: 74.1 %

Procedure:
A suspension of 6-methylisocytosine (0.98 g, 7.8 mmol), and 2-isocyanatoethyl methacrylate (2.20 g, 14.1 mmol) in dry pyridine (35 mL) was heated under reflux for 2 h, giving a clear solution. Cooling induced the formation of crystals. Acetone was added (20 mL), and the resulting microcrystalline powder was filtered. Recrystallization from ethanol/CHCl3 (1:1, v/v) gave analytically pure product (1.62 g, yield is 74%) 1H NMR (400 MHz, CDCl3) 13.00 (s, 1H, intramol H-bonding), 11.97 (s, 1H, CH2—NH—CO), 10.53 (s, 1H, CH2—NH—CO—NH), 6.20 (s, 1H, CHH═C), 5.80 (s, CCH3CH—CO), 5.56 (s, 1H, CHH═C), 4.31-4.28 (t, j=5.6, 2H, OCH2CH2N), 3.62-3.58 (q, J=5.6 Hz, 2H, OCH2CH2N), 2.26 (s, 3H, CH3-C-NH), 1.96 (s, 3H, CH3—C═CH2), IR (neat) 3250-2800, 1726, 1699, 1664, 1641, 1583, 1521, 1253, 1172, 939 cm-1; Melting point Tm=206.7° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:28])[C@@H:17]([NH:18]C(=O)CC3C=CC=CC=3)[C@H:4]2[S:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[Na+].P([O-])([O-])(O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1.O.CO>[NH2:18][C@@H:17]1[C:16](=[O:28])[N:5]2[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:9])[C:2]([CH3:29])([CH3:1])[S:3][C@H:4]12
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1NC(=O)OCC(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2C1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 11.0 g of 2,2-dimethyl-6β-(N-phenylacetyl-amino)-3-(N-2,2,2-trichloroethoxycarbonyl-amino)-penam in a mixture of 240 ml of anhydrous methylene chloride and 25.6 ml of pyridine is treated with 166 ml of a 10% strength solution of phosphorus pentachloride in methylene chloride under a nitrogen atmosphere -10° C., and is subsequently stirred for 30 minutes at 0° C. 120 ml of absolute methanol are then added whilst cooling strongly (-10° C.) and the mixture is stirred for a further 2 hours. 80 ml of water are added, the pH value (measured in samples diluted with water) is adjusted to 3.3 with about 9 ml of a 2N aqueous sodium hydroxide solution, and the reaction is allowed to continue for one hour at 0° C. and a further hour at 20° C. The mixture is then poured out into 500 ml of a 1M aqueous dipotassium hydrogen phosphate buffer solution whilst stirring, and the pH value is adjusted from 6.5 to 7.0 by adding 50% strength aqueous tripotassium phosphate solution. The aqueous phase is separated off and twice washed with 200 ml of methylene chloride at a time; the three organic solutions are each twice washed with water, combined, dried over sodium sulphate and evaporated under reduced pressure. The crystalline residue is taken up in 40 ml of a 1:1 mixture of benzene and hexane; the mixture is cooled for 15 minutes at 0° C. and the precipitate is filtered off. 6β-Amino-2,2-dimethyl-3-(N-2,2,2-trichloroethoxycarbonyl-amino)-penam is thus obtained, melting at 179°-180° C. (corrected); infrared absorption spectrum: characteristic bands (in methylene chloride) at 2.90μ, 5.58μ, 6.62μ, 7.17μ, 7.27μ, 8.32μ, 8.46μ, 8.82μ, 9.25μ, and 9.62μ; (in Nujol) at 2.95μ, 3.01μ, 3.11μ, 5.64μ, 5.80μ, 6.35μ, 7.60μ, 7.87μ, 8.00μ, 8.27μ, 8.65μ, 8.70μ, 9.16μ, and 9.57μ; thin layer chromatogram (silica gel): Rf=0.17 (in the system toluene/acetone, 8:2) and Rf=0.43 (in the system toluene/acetone, 6:4); characteristic yellow colouration with ninhydrine-collidine (free amino group).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29](Br)=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:28]=[CH:27][C:26]([NH2:25])=[N:31][C:30]=3[CH3:32])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(N)ccc1C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 6-amino-3-bromo-2-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (65 mg, 15%). MS (ISP) 444.3 [(M+H)+]; mp 243-246° C.
Reaction SMILES: [OH:1][C:2]1N=C2C=C(OCC3SC=C(C(C)C)N=3)C=CN2C(=O)C=1.[CH2:23]([C:25]1[CH:26]=[C:27]([CH2:30][CH2:31][C:32]2[CH:48]=[CH:47][N:35]3[C:36](=[O:46])[CH:37]=[C:38]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[N:39]=[C:34]3[CH:33]=2)[S:28][CH:29]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[C:27]([CH2:30][CH2:31][C:32]2[CH:48]=[CH:47][N:35]3[C:36](=[O:46])[C:37]([CH:2]=[O:1])=[C:38]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)[N:39]=[C:34]3[CH:33]=2)[S:28][CH:29]=1)[CH3:24]
Reactant: CCc1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)c1
Reactant: CC(C)c1csc(COc2ccn3c(=O)cc(O)nc3c2)n1
Product: CCc1csc(CCc2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)c1

Procedure:
Reactions were performed in the same manner as in Example 1, (I) by using 8-[2-(4-ethyl-2-thienyl)ethyl]-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (122 mg, 0.33 mmol) as a starting material. As a result, 52 mg (40% for the three steps) of the title compound in orange color was obtained.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:56][O:57][C:58](=[O:64])[C:59]([NH2:63])([CH3:62])[CH2:60][CH3:61]>CN(C=O)C>[CH3:56][O:57][C:58](=[O:64])[C:59]([CH3:62])([NH:63][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[CH2:60][CH3:61]
Reactant: CCC(C)(N)C(=O)OC
Reactant: O=C(O)c1ccc2ccccc2c1OCCOc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccccc1)C(=O)OC
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 487 mg 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid in 6 ml abs. DMF under inert atmosphere 216 mg 1-hydroxybenzotriazole, 306 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 293 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 252 mg of 2-amino-2-methyl-butyric acid methyl ester hydrochloride, followed by 293 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by chromatography on silica (ethyl acetate/heptane) to yield 419 mg of 2-methyl-2-{[1-(2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-butyric acid methyl ester.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17](=[NH:20])SC)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[N:21]#[C:22][NH2:23].O.C(OCC)(=O)C>CN(C)C=O>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17]([NH2:20])=[N:23][C:22]#[N:21])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: N#CN
Reactant: CSC(=N)NCc1ccc2c(c1)Nc1nccnc1S2
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CN=C(N)NCc1ccc2c(c1)Nc1nccnc1S2
Yield: 77.1 %

Procedure:
450 mg of N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-S-methylisothiourea and 500 mg of cyanamide were heated in 30 ml of N,N-dimethylformamide to 70° C. for 12 hours. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted and washed with water. After adding 5 g of silica gel, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 340 mg of the title compound as yellow crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=1>C(#N)C.O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:14]([CH3:15])[CH3:16])[C:9]([OH:13])=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[CH3:12]
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC#N
Solvent: O
Product: Cc1c(Cl)cc(C(C)C)c(O)c1[N+](=O)[O-]
Reaction time: 0.83 h
Yield: 81.9 %

Procedure:
Acetyl nitrate obtained by mixing acetyl anhydride (1.12 g, 11 mmol) with fuming nitric acid (693 mg, 11 mmol) at 0° C. was dropped into a solution of 4-chloro-2-isopropyl-5-methylphenol (1.84 g, 10 mmol) in acetonitrile (20 ml) at 0° C. followed by stirring for 50 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (80 g of silica gel; developing solvent, hexane:methylene chloride=30:1→10:1) to provide 1.88 g (yield 83%) of 4-chloro-6-isopropyl-3-methyl-2-nitrophenol as pale yellow crystals.