Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:11]([C:8]4[CH:7]=[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[O:10][N:9]=4)=[O:13])[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc(-c2cccs2)on1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc(-c5cccs5)on4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
5-Thiophen-2-yl-isoxazole-3-carboxylic acid (43 mg, 0.22 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by 1-hydroxybenzotriazole (32 mg, 0.24 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47 mg, 0.25 mmol, 1.15 eq) and N,N-diisopropylethylamine (83 μL, 0.48 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 5-thiophen-2-yl-isoxazole-3-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide as an orange solid (15 mg, 13% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][Cl:23].C([Li])CCC.S([O-])(O)(=O)=O.[K+]>CCCCCC.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([CH2:22][Cl:23])([OH:20])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Reactant: ClCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1COC(O)(CCl)[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (0.34 g) and bromochloromethane (0.10 ml) were added to dehydrated tetrahydrofuran (12 ml). After cooling to −78° C., 1.53 M solution (1.03 ml) of n-butyllithium in hexane was added to the obtained mixture, and they were stirred for 1 hour. 10% aqueous potassium hydrogensulfate solution was added to the reaction mixture to terminate the reaction. The temperature of the reaction mixture was elevated to room temperature. After the extraction with ethyl acetate twice, the obtained ethyl acetate layer was dried over anhydrous magnesium sulfate and then magnesium sulfate was removed. The solvent was evaporated under reduced pressure to obtain intended (4S)-N-tert-butoxycarbonyl-5-chloromethyl-5-hydroxy-4-phenylmethyloxazolidine (0.40 g) in a yield of 100%.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:15][CH:14]([CH3:16])[CH2:13][CH:12]([NH:11][C:8]1[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[N:10][CH:9]=1)[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(Nc1cnc(C(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
(+/−)-5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid methyl ester (617 mg, 1.39 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (2 mL), and 1.0 M NaOH (6 mL, 6 mmol) was added. This was stirred at 50° C. for 2.5 h before cooling and bringing to pH 3 with 1 N HCl. This was extracted three times with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give (+/−)-5-[3-methyl-1-(4′-trifluoromet hyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid with ethyl acetate (0.636 g) as clear foam. 1H NMR (400 MHz, DMSO-d6, δ): 8.18 (s, 2 H) 7.84-7.91 (m, 2 H) 7.75-7.81 (m, 2 H) 7.71 (d, J=8.2 Hz, 2 H) 7.55 (d, J=8.2 Hz, 2 H) 7.42 (d, J=7.8 Hz, 1 H) 4.63-4.74 (m, 1 H) 1.74-1.85 (m, 1 H) 1.67 (dt, J=13.1, 6.5 Hz, 1 H) 1.51-1.61 (m, 1 H) 0.98 (d, J=6.4 Hz, 3 H) 0.93 (d, J=6.4 Hz, 3 H); MS (M+1): 430.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH3:38][NH:39][C:40]([N:42]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=1)[NH2:43])=[O:41].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:43][N:42]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=2)[C:40]([NH:39][CH3:38])=[O:41])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CNC(=O)N(N)Cc1ccc(C)c(C)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2ccc(C)c(C)c2)C(=O)NC)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl] butyric acid (1.46 g, 4.96 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl chloride (474 μL, 5.46 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (30.6 μL, 0.39 mmol). Completion of acid chloride formation was verified by HPLC. This solution was then added dropwise to a suspension of N-Methyl-1-(3,4-dimethylphenylmethyl)hydrazine carboxamide methanesulfonate (1.50 g, 4.95 mmol) and pyridine (1.00 μL, 12.9 mmol) in ethyl acetate (15 mL) at 0° C. After stirring at 0° C. for 6 h, the solution was warmed to rt and washed with 1N HCl (2×20 mL), 5% aq. NaHCO3 (2×20 mL) and sat'd aq. NaCl. The organic layer was dried (MgSO4), filtered and concentrated to a yellow oil. The oil was purified by column chromatography (SiO2, 9:1 ethyl acetate:hexanes), to afford the title compound as a clear oil (1.48 g, 62%): 1H NMR (DMSO-d6, 60° C.) δ 9.42 (s, 1H), 6.97 (m, 5H), 6.71 (d, 2H, J=8 Hz), 6.23 (s, 1H), 4.46 (s, 2H), 4.15 (q, J=7 Hz), 2.59 (s, 3H), 2.43 (t, 2H, J=8 Hz ), 2.15 (s, 6H), 2.06 (t, 2H, J=8 Hz ), 1.70 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.17 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 172.0, 158.7, 153.8, 136.4, 136.0, 135.9, 135.4, 130.2, 129.9, 129.7, 126.5, 119.5, 79.2, 61.6, 50.6, 34.4, 33.5, 27.6, 27.2, 25.7, 20.0, 19.7, 14.6; IR (CHCl3) 3009, 1669, 1509, 1142 cm−1; Exact Mass Calcd. for C27H38N3O5: 484.2811. Found: 484.2822.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C1CCc2cc(-n3cccn3)ccc21
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Combine 5-fluoro-indan-1-one (1.02 g, 6.79 mmol), pyrazole (0.46 g, 6.79 mmol), and potassium carbonate (1.03 g, 7.47 mmol, 1.10 equivalents) in dimethyl sulfoxide (5 ml) in a sealed tube and heat to 100° C. for 48 hours. Cool to room temperature, dilute with ether, wash with water (2×), dry over anhydrous sodium sulfate, and concentrate to obtain the title compound as a brown solid (0.98 g, 73%). LC-MS m/z 199.1 (M++1).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]Cl)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C1(C)C=CC=CC=1.O>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12](=[CH2:15])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CCl)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=C1CCN(C(=O)c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.50 g (6.32 mmol) of N-benzoyl-4-chloromethylpiperidine (D). The resulting solution was cooled to 5° C. and thereto was added 1.36 g (25.28 mmol) of sodium methoxide. After stirring at 60° C. for 4 hours, the reaction mixture was cooled down to room temperature and then poured into a mixed liquid of 40 ml of toluene and 40 ml of iced water. An organic layer was separated and dried over 2 g of anhydrous magnesium sulfate and, thereafter, the solvent was removed by distillation. The residual liquid was subjected to silicagel column chromatography (stationary phase: 50 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (2:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.00 g of N-benzoyl-4-methylenepiperidine (E) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][NH:17][C:18](=O)[CH2:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([OH:22])[CH2:16][NH:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)NCC(O)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCNCC(O)c1ccc(OCc2ccccc2)cc1
Yield: 97.8 %

Procedure:
To the amide from example 25 (27.5 g, 0.092 mol) in dry THF (100 ml) was added borane-methyl sulphide complex (17.5 ml, 0.18 mol) and the reaction mixture was stirred at reflux for 2 hours. The reaction mixture was cooled then quenched with methanol (30 ml). Water (50 ml) and c.HCl (35 ml) were added and the reaction mixture stirred until all bubbling ceased before concentrating in vacuo. To the residue water (250 ml) was added, before basifying by addition of NH4OH (30 ml). The aqueous layer was extracted with ethyl acetate (3×200 ml) and the combined organic extracts dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a white solid (26.1 g, 0.09 mol, 99%). 1H NMR (CD3OD, 400 MHz) δ: 0.95 (t, 3H), 1.58 (q, 2H), 2.62 (m, 2H), 2.81 (m, 2H), 4.72 (dd, 1H), 5.05 (s, 2H), 6.95 (d, 2H), 7.24 (m, 3H), 7.35 (t, 2H), 7.41 (d, 2H). LRMS: m/z 286 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: ON=Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a suspension of 4-chlorobenzaldehyde (70 g, 0.50 mol) and hydroxylamine hydrochloride (38.06 g, 0.55 mol) in a mixture of water (125 ml), methanol (150 ml) and ice (215 ml) was added an aqueous solution of sodium hydroxide (43.82 g NaOH in 100 ml water). Ice was occasionally added to keep the temperature below room temperature. The resulting almost clear solution was stirred for two hours before it was extracted with methyl t-butyl ether (500 ml). The remaining aqueous layer was acidified with 6 N HCl (95 ml) to pH around 5. The suspension was extracted with dichloromethane (500 ml). The organic phase was dried and concentrated to give the title compound as a white solid (63.39 g): NMR (CDCl3, 200 MHz): δ=8.09 (s, 1H), 7.66 (br s, 1H), 7.49 (m, 2H), 7.34 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[N:5]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:50][CH3:51].O>CN(C=O)C>[CH2:50]([O:1][CH2:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[N:5]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:4]=1)[CH3:51]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(CO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Yield: 100 %

Procedure:
The solution of (R)-1-(3-(hydroxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (124 mg, 0.224 mmol), cesium carbonate (146 mg, 0.448 mmol) and iodoethane (26.9 μl, 0.336 mmol) in DMF was stirred at 60° C. for 24 h. Water was added into the solution and extracted with EtOAc for twice. The combined organic extracts were washed with water, brine and dried over Na2SO4. After concentration (R)-1-(3-(ethoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (130 mg, 0.224 mmol, 100% yield) was yielded without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](N)=[C:7]([Cl:13])[CH:6]=1)[CH3:2].CS(O)(=O)=O.N(OCCC(C)C)=O.[SH:28][CH2:29][C:30]([OH:32])=[O:31]>C(O)(=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([S:28][CH2:29][C:30]([OH:32])=[O:31])=[C:7]([Cl:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=C(O)CS
Agent: CC(C)CCON=O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Cl)c(SCC(=O)O)c(Cl)c1
Reaction time: 0.5 h

Procedure:
4-Amino-3,5-dichlorobenzoic acid ethyl ester (17.7 g) was dissolved in a mixture of acetic acid (75 mL) and dichloromethane (75 mL) and then methanesulfonic acid (22 mL) was added. 3-Methylbutyl nitrite (10 mL) was added to the solution while the temperature was kept at 0-5° C. After 30 min, mercaptoacetic acid (38 mL) was added at 0-5° C. Then a part of the dichloromethane was removed by distillation which was stopped when the internal temperature of the mixture was 80° C. and this temperature was kept for additional 45 min. The mixture was cooled and the rest of the solvents were evaporated under vacuum. Toluene (300 mL), water (200 mL) and hydrochloric acid (6 M, 80 mL) were added. The organic phase was separated and then extracted with potassium bicarbonate solution (1 M, 200 mL) which was acidified with hydrochloric acid (6M, 50 mL). The product was extracted to toluene (100 mL) which was dried (sodium sulphate) and evaporated to dryness (yield 5.1 g). 1H-NMR (400 MHz, DMSO-d6) d=1.33 (t, J=7.0 Hz, 3H), 3.74 (s, 2H), 4.34 (q, J=7.0 Hz, 2H), 7.97 (s, 2H), 12.5 (b, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([NH:70][CH2:71][CH2:72][CH2:73][NH:74][CH2:75][CH3:76])=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]([CH2:73][CH2:72][CH2:71][NH2:70])[CH2:75][CH3:76])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCNCCCNC(=O)OC(C)(C)C
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCCN)C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-(3-tert.-butyloxycarbonylamino-propyl)-ethylamine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:23][NH:24][O:25][CH3:26].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([N:24]([O:25][CH3:26])[CH3:23])=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNOC
Reactant: CCn1ncc2c(NC3CCCCC3)c(C(=O)O)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C(=O)N(C)OC)cnc21
Reaction time: 1 h

Procedure:
4-Cyclohexylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.200 gm, 0.0006 mole) (example 5) and N,O-dimethylhydroxylamine hydrochloride (0.102 gm, 0.0010 mole) were taken in dimethylformamide. At 0° C., hydroxybenzotriazole (0.162 gm, 0.0012 mole) and N-methylmorpholine (0.30 ml, 0.0027 mole) were added and the reaction mixture was stirred for about 1 h. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.266 gm, 0.0012 mole) was added and the reaction mixture was stirred for about 14 h. Water was added and extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The compound was purified over preparative thin layer chromatography.
Reaction SMILES: [H-].[Na+].C1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)OC1.[CH2:19]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]Cl)[CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>COCCOC.C(Cl)(Cl)Cl.CO.CO>[CH2:19]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][N:8]2[CH2:7][C:6](=[O:18])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9]2(=[O:16])=[O:17])[CH2:29][CH2:28]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCCCN1CCC(OCc2ccccc2)CC1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: CO
Product: O=C1CN(CCCN2CCC(OCc3ccccc3)CC2)S(=O)(=O)c2ccccc21
Temperature: 50 °C
Yield: 48.9 %

Procedure:
In 1,2-dimethoxyethane (40 mL) was suspended 60% sodium hydride (180 mg, 4.5 mmol.), and then 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (1.00 g, 4.1 mmol.) was added to the suspension. The suspension was heated for 1 hour under stirring. The reaction liquid was cooled to 50° C., and to this was added a solution of 4-benzyloxy-1-(3-chloropropyl)piperidine (1.11 g, 4.1 mmol.) in 1,2-dimethoxyethane (10 mL). The mixture was further heated for 20 hours under refluxing. The reaction liquid was filtered to remove insolubles and the solvent was distilled off to give a residue. To the residue were added aqueous 9% hydrochloric acid (30 mL) and methanol (30 mL), and the mixture was heated for 15 min. under refluxing. The reaction liquid was placed under reduced pressure to distill methanol off. The residue was treated with ice-water, and the deposited oil was extracted with dichloromethane. The dichloromethane portion was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to leave a residue. The residue was treated by silica gel column chromatography (chloroform/methanol=30/1) to give the desired compound (860 mg, yield 45%) as a red oil.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].CC([O-])(C)C.[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CS(C)=O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)Oc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Oc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of 3-[(1-methylethyl)oxy]phenol (Intermediate 27, 456 mg) in DMSO (8 mL) was added t-BuOK (336 mg, 3 mmol, Acros). The reaction mixture was stirred at 20° C. for 30 minutes. 2-chloro-5-nitropyridine (474 mg, 3 mmol, Aldrich) was added and the resulting mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ice-water (50 mL) and extracted with dichloromethane (3 times 50 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with (PE:EtOAc=50:1) to afford the title compound as a light yellow solid (670 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:14])=[CH:5][CH:4]=1.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([CH2:7][OH:8])[C:10]=1[C:9]([N:16]([CH3:17])[CH3:15])=[O:14]
Reactant: COc1ccc2c(c1OC)C(=O)OC2
Reactant: CNC
Solvent: CCO
Product: COc1ccc(CO)c(C(=O)N(C)C)c1OC
Yield: 100 %

Procedure:
A mixture of 30 g of 6,7-dimethoxy 3H-isobenzofuranone, prepared according to the method described in Example IV, 1 liter of ethanol and 300-400 cm3 of dimethylamine was agitated for several hours and then evaporated under vacuum at 30° - 35° C. The crystallized product was washed with heptane. The 2,3-dimethoxy N,N-dimethyl 6-hydroxymethyl benzamide was obtained in a yield of 100%. F = 90° C.
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[C:9]([CH3:11])=[CH2:10].N[C:17]1[N:21]([C:22]2[C:30]([Cl:31])=[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][N:24]3[N:23]=2)[N:20]=[CH:19][C:18]=1[C:32]#[N:33].[ClH:34]>C(#N)C>[CH2:14]([O:13][C:8](=[O:12])[C:9]([Cl:34])([CH3:11])[CH2:10][C:17]1[N:21]([C:22]2[C:30]([Cl:31])=[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][N:24]3[N:23]=2)[N:20]=[CH:19][C:18]=1[C:32]#[N:33])[CH3:15]
Reactant: C=C(C)C(=O)OCC
Reactant: Cl
Reactant: N#Cc1cnn(-c2nn3c(c2Cl)CCCC3)c1N
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)C(C)(Cl)Cc1c(C#N)cnn1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.6 g (15.5 mmol) tert-butyl nitrite, 20 ml ethyl methacrylate and 1.52 g copper-ll-chloride is added to 20 ml acetonitrile and 2.62 g (10 mmol) 5-amino-1-(3-chlor-4,5,6,7-tetrahydropyrazolo-[1,5-a]-pyridin-2-yl)-4-pyrazol-carbonitrile is added in 3 portions. The mixture is stirred at room temperature for 20 hours, added to 50 ml 2N hydrochloric acid, extracted 3 times with dichloromethane, dried over magnesium sulphate and concentrated. Purification is by column chromatography using a hexane/ethyl acetate mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18]>C(#N)C>[CH3:14][P:15]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])(=[O:19])[O:16][CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOP(C)OCC
Solvent: CC#N
Product: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-1,2-dinitrobenzene (3.31 mmol) and diethyl methylphosphonite (5.30 mmol) in 3 ml of acetonitrile is stirred at RT overnight. The mixture is then concentrated and the residue is purified by preparative TLC to yield ethyl P-methyl-2-nitro-5-chlorophenylphosphinate.