Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])[CH2:7][CH2:6]2)[O:4]CC1.Cl.CC(C)=O>O>[OH:15][C:13]([CH3:16])([CH3:14])[CH2:12][O:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: CC(C)(O)COC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)COC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A mixture of 1-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-methylpropan-2-ol (5.53 g), 3N hydrochloric acid (30 mL) and acetone (30 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→60/40 (volume ratio)] to give the title compound as a colorless oil (3.25 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCN1CCOCC1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: Nc1nc(NCCN2CCOCC2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 4-(2-aminoethyl)morpholine in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: C(OC([N:8]1CCN(CCCN)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:18]([O:22][C:23]([N:25]1[CH2:32][CH:31]2[CH:27]([CH2:28][NH:29][CH2:30]2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]2[CH:31]([CH2:30][N:29]([CH2:10][CH2:9][NH2:8])[CH2:28]2)[CH2:32]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Product: CC(C)(C)OC(=O)N1CC2CN(CCN)CC2C1

Procedure:
Using the method of 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester, the title compound is synthesized from hexahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:7][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: CCOc1ccc(Cc2cc(Br)c(OC)cc2OC)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 5-bromo-2,4-dimethoxybenzaldehyde and 4-bromophenetole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.O=[C:11]([C:17](OCC)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17](=[O:18])[NH:8]2
Reactant: Nc1cccc(Cl)c1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2c(Cl)cccc2[nH]c1=O
Temperature: 25 °C
Yield: 56.5 %

Procedure:
10.5 g (73.6 mmol) of 3-chloro-1,2-phenylenediamine and 12.8 g (73.5 mmol) of diethyl ketomalonate were dissolved in ethanol, and the solution was heated to reflux for 3 hours. While heating to reflux, ethanol was added thereto until precipitated crystals dissolved. The reaction mixture was cooled to room temperature, and then precipitated crystals were separated by filtration. The filter cake was washed with cold ethanol, and then dried, to obtain 10.5 g (yield: 51%) of ethyl 5-chloro-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as pale yellow acicular crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N)cc1C(F)(F)F

Procedure:
The title compound is prepared from 1-methoxy-4-nitro-2-trifluoromethyl-benzene (1 g, 4.43 mmol) by hydrogenation (5→1.4 bar) in the presence of Raney-Ni (0.3 g) in MeOH (20 mL) during 15 h. The product is isolated by filtration of the reaction suspension over Hyflo and evaporation of the solvent under reduced pressure to give compound of Stage 149.1 as a beige solid: M+H=191.9; Rf (AcOEt/hexane=1:1): 0.33.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:22][OH:23])([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(O)C>CO>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:17][OH:18])([CH2:22][OH:23])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CO)(CCOCc1ccccc1)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: OCC(CO)(CO)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
1.03 g (3.24 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)-2-hydroxymethylmalonate was dissolved in 10 mL of methanol, and this was added dropwise to 1.69 g (44.6 mmol equivalents) of sodium borohydride over 20 minutes. This was refluxed while heating overnight and then cooled to room temperature (25° C.). Water was added to the reaction liquid, and a reaction was carried out for 30 minutes. The reaction liquid was washed with chloroform, and the aqueous phase was concentrated under vacuum. 100 mL of ethanol was added to the obtained residue, and the mixture was refluxed while heating for 2 hours. Immediately after completion of the reaction, the mixture was subjected to silica gel column chromatography (eluent: ethanol) to give 543 mg of 4-benzyloxy-2,2-dihydroxymethylbutanol as an crude product.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[N:24]1([CH:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[CH2:19][CH2:20]2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
25 mL TFA were added at RT to 16.0 g (39.7 mmol) tert-butyl 4-(1-benzyloxycarbonyl-piperidin-4-yl)-piperazine-1-carboxylate in 200 mL DCM and the reaction mixture was stirred overnight at RT. It was evaporated down i. vac., the residue was taken up in 200 mL water and 200 mL EtOAc, the aqueous phase was separated off, combined with 50 mL 15% K2CO3 solution, extracted twice with 200 mL EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was reacted with any further purification.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CC#N.[ClH:28]>CCOCC.CCOC(C)=O.O>[ClH:28].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Yield: 64 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (6.0 g, 25 mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), K2CO 3 (3.5 g) and CH3CN (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into H2O, and after extractive workup with EtOAc, 6.0 g of an orange oil was realized. The oil was dissolved in Et2O and ethereal HCl was added to precipitate 6.3 g of a white hydrochloride salt. The salt was recrystallized from CH3CN to yield 6.0 g (64%) of the desired compound. An analytical sample was obtained by recrystallization of a 1.0 g sample from EtOH-Et2O to yield 0.8 g of a white solid, m.p.=197°-199° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:27])[C:21](=[CH:25][CH:26]=1)[C:22](O)=[O:23]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:22](=[O:23])[C:21]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)[NH:27][C:15]2=[O:16])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C=CCOc1ccc(S(=O)(=O)N=C=O)cc1
Product: C=CCOc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 54.3 %

Procedure:
1.50 g (7.03 mmol) of 4-allyloxybenzenesulfonyl isocyanate and 1.2 g (7.03 mmol) of 4-chloroanthranilic acid were treated in the same way as in Preparation Example 5 to obtain 1.5 g (yield 53%) of 3-(4-allyloxybenzenesulfonyl)-7-chloro -2,4(1H,3H)-quinazolinedione. 500 mg (1.27 mmol) thereof was similarly treated to obtain 405 g of the above-identified compound (yield 90%). Properties: colorless crystal, Melting point: >200° C. decomposition), PMR (δ ppm, DMSO-d6): 6.98 (2H, d), 7.11 (1H, s), 7.23 (1H, d), 7.85 (1H, d), 8.00 (2H, d), 11.25 (1H, br).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1CCC(NC(=O)O[C:18]([CH3:21])([CH3:20])[CH3:19])CC1>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:19][CH:18]1[CH2:21][CH2:20]1
Reactant: Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Brc1ccccc1NCC1CC1

Procedure:
Example 142A was prepared as described in Example 111A substituting cyclopropanecarbaldehyde for Example 105B and 2-bromoaniline for tert-butyl piperidin-4-ylcarbamate. The isolated product was purified by flash chromatography (silica gel, 0-10% ethyl acetate in heptane) to give the title compound.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][C:19]1[S:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][N:23]=1)[P:10]([O:15]CC)(=[O:14])[O:11]CC)(=[O:8])[O:5]CC)C.Cl>CO>[C:24]1([C:21]2[S:20][C:19]([NH:18][CH:9]([P:10]([OH:14])(=[O:11])[OH:15])[P:4]([OH:8])(=[O:3])[OH:5])=[N:23][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(OCC)C(Nc1ncc(-c2ccccc2)s1)P(=O)(OCC)OCC
Agent: Cl
Solvent: CO
Product: O=P(O)(O)C(Nc1ncc(-c2ccccc2)s1)P(=O)(O)O
Temperature: 25 °C

Procedure:
4.02 g (8.7 mmol) of 1-(5-phenylthiazol-2-yl-amino)methane-1,1-diphosphonic acid tetraethyl ester are heated under reflux in 30 ml of N hydrochloric acid for 18 hours. After cooling to room temperature, a small quantity of methanol is added and the whole is filtered. The filtrate is heated under reflux in methanol for 1 hour, filtered while hot and washed twice with hot methanol. Yield: 2.90 g (95% of the theoretical yield) of 1-(5-phenylthiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 290° (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12]Br>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12][O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1]
Reactant: CN(C)CCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-(N,N-dimethylamino)ethanol (1.319 g, 4.92 mmol) was dissolved in N,N-dimethylformamide (16 ml). Sodium hydride (60%, 335 mg, 8.37 mmol) was added and the mixture was stirred at ambient temperature for about twenty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (1.319 g, 4.92 mmol) as a solution in N,N-dimethylformamide (3 ml). The resulting mixture was stirred at ambient temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed with brine (7×) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:16](O)=[O:17])=[CH:10][C:11]=2[O:13][CH2:14][CH3:15])[N:6]([CH:19]2[CH2:21][CH2:20]2)[CH:5]=1)(=[O:3])[NH2:2].Cl.[CH3:23][O:24][C:25](=[O:48])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][C:35]3=[O:47])[CH:27]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:16]([N:40]3[CH2:39][CH2:38][C:37]4([CH2:36][C:35](=[O:47])[C:34]5[C:44](=[CH:45][CH:46]=[C:32]([C:28]6[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=6)[C:25]([O:24][CH3:23])=[O:48])[CH:33]=5)[O:43]4)[CH2:42][CH2:41]3)=[O:17])=[CH:10][C:11]=2[O:13][CH2:14][CH3:15])[N:6]([CH:19]2[CH2:21][CH2:20]2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: CCOc1cc(C(=O)O)cc2c1c(C(N)=O)cn2C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cccc(C(=O)OC)c4)ccc2O3)cc2c1c(C(N)=O)cn2C1CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.22 mL) was added to a solution of 3-carbamoyl-1-cyclopropyl-4-ethoxy-1H-indole-6-carboxylic acid (229 mg), 3-(4-oxo-spiro[chroman-2,4′-piperidin]-6-yl)benzoic acid methyl ester hydrochloride (306 mg), WSC hydrochloride (166 mg) and HOBT (133 mg) in DMF (4 mL), and the mixture was stirred at 60° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, then washed successively with water, aqueous saturated sodium bicarbonate and saturated saline water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified through silica gel column chromatography (chloroform/methanol) to obtain the intended ester derivative as a colorless amorphous substance. 1H-NMR (400 MHz, CDCl3) δ: 8.71 (1H, s), 8.25 (1H, dd, J=1.5, 1.5 Hz), 8.14 (1H, d, J=2.4 Hz), 8.04-8.00 (2H, m), 7.83-7.74 (2H, m), 7.51 (1H, dd, J=7.8, 7.8 Hz), 7.37 (1H, d, J=1.5 Hz), 7.13 (1H, d, J=7.8 Hz), 6.74 (1H, d, J=1.5 Hz), 5.54 (1H, s), 4.62-4.41 (1H, br m), 4.29 (2H, q, J=7.0 Hz), 3.95 (3H, s), 2.28-1.71 (4H, br m), 3.88-3.32 (4H, br m), 2.82 (2H, s), 1.55 (3H, t, J=7.0 Hz), 1.16-1.00 (4H, m); MS [M+H]+=622.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(S)c1
Reactant: O=Cc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1cccc(Sc2cccc(C=O)c2)c1
Yield: 83.9 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzaldehyde (232 mg, 1.0 mmol), 3-methoxythiophenol (124 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-(3-methoxyphenyl)sulfanylbenzaldehyde (205 mg, 85% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=15/1). Rf=0.4 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 9.91 (s, 1 H), 7.76-7.77 (m, 1 H), 7.71 (dt, 1 H, J=1.2 Hz, 7.2 Hz), 7.45-7.53 (m, 1 H), 7.42 (t, 1 H, J=7.5 Hz), 7.25 (t, 1 H, J=7.5 Hz), 6.91-6.98 (m, 2 H), 6.84 (ddd, 1 H, J=1.2 Hz, 2.4 Hz, 8.1 Hz), 3.77 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 191.7, 160.3, 138.4, 137.3, 135.8, 135.0, 131.1, 130.5, 129.9, 127.9, 124.6, 117.6, 114.0, 55.7. IR (neat, cm−1) 3060, 3006, 2960, 2937, 2834, 2726, 1698. MS (EI) m/z (relative intensity) 244 (100), 227 (30), 211 (40). Anal. Cald. for C14H12O2S, Cald. C, 68.83; H, 4.95. Found C, 69.04; H, 4.94.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].C(O)=O.CS(O)(=O)=O>O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Agent: CS(=O)(=O)O
Solvent: O=CO
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(C(=O)O)nn12
Reaction time: 1 h

Procedure:
5.8 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-carbethoxy-s-triazolo[4,3-b]pyridazine were heated under reflux with 18.3 ml. 90 percent aqueous formic acid and 2.75 ml. methane-sulfonic acid for 3 hours at a bath temperature of 130° C. 80 ml. water were then added thereto and the precipitated crystals were filtered off with suction, after having stood for 1 hour, and washed with water. There were thus obtained 4.85 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-carboxy-s-triazolo[4,3-b]pyridazine, which has a melting point of 257° - 260° C. 1 g. of the product was recrystallized from 15 ml. dioxan with the addition of charcoal, to give 0.6 g. of pure product which melts, with foaming up, at 260° - 262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:19]1[CH2:21][CH2:20]1)O.CCN(CC)CC.O=S(Cl)Cl.[CH2:33]([Mg]Br)[CH:34]([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:19]1[CH2:21][CH2:20]1)[CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(C2CC2)N1CC(F)(F)F
Reactant: CC(C)C[Mg]Br
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CC1(C2CC2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 0° C. solution of 0.08 g (0.25 mmol) 6-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 3 mL toluene was added 0.17 mL (1.25 mmol) Et3N and 0.018 mL (0.25 mmol) SOCl2. After 20 min at 0° C. 1 mL (1 mmol, 1M solution in ether) isobutyl magnesium bromide was added and the reaction mixture was stirred 30 minutes before an additional 0.5 mL (0.5 mmol) isobutyl magnesium bromide was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with 75 mL saturated aqueous NH4Cl solution and extracted with 100 mL EtOAc. The extract was washed with 75 mL brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1×10 cm silica gel, linear gradient 10-35% EtOAc/hexanes) followed by preparative HPLC (YMC C18 PRO20×150 mm, linear gradient 5-95% CH3CN/H2O 0.05% added TFA, over 30 min) to afford afforded 6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) 8.17 (s, 1H); 7.43 (d, J=2.20 Hz, 1H); 7.15 (dd, J=2.38 and 8.61 Hz, 1H); 6.62 (d, J=8.42 Hz, 1H); 4.50 (dq, J=15.4 and 8.61 Hz, 1H); 3.96 (dq, J=15.4 and 8.60 Hz, 1H); 1.56 (m, 1H); 1.41 (dd, J=14.8 and 5.31 Hz, 1H); 1.23 (dd, J=14.8 and 5.68 Hz, 1H); 0.88 (m, 1H); 0.80 (d, J=6.59 Hz, 3H); 0.78 (m, 1H); 0.69 (m, 2H); 0.55 (d, J=6.59 Hz, 3H). High resolution mass spec (FT/ICR): calc M+H=361.1289, found 361.1283.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 91, 100.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded the title compound as a colorless solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N+:7]=1[O-].[N+]([O-])=O.O.N>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=[C:8]([Cl:12])[N:7]=1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[N+][O-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 95% concentrated nitric acid (21 mL) and 98% concentrated sulfuric acid (50 mL) was added 2,6-dichloropyridine-N-oxide (12.8 g, 78 mmol). After the reaction was performed at 148° C. by stirring for 1 h, it was continued when the temperature was increased to 156° C. until no nitrogen dioxide was released. The reaction solution was cooled to room temperature, poured into 150 g ice water, and adjusted to pH=6 with ammonia water to precipitate a solid product. It was subjected to suction filtration. The resultant crude product was recrystallized with petroleum ether to afford 10 g yellow solid with a yield of 66.4%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[N+:19]([O-:21])=[O:20].[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23]>C1COCC1>[CH2:22]([CH:24]([NH:27][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(N)CC
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2[N+](=O)[O-])c(C)n1
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Nc2c(C)cc(C)nc2C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a cooled solution of (6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amine (88 mg, 0.29 mmol) in 1 ml of dry THF was added 1-ethyl-propyl-amine (80 mg, 0.92 mmol) at -78° C. The mixture was stirred at that temperature for 3 hrs, then warmed to -10° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (88 mg, 86%) as an orange solid, mp 151-152° C. 1H NMR (CDCl3) δ9.16 (d, 1H), 6.92 (s, 1H), 4.35 (m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.5-1.80 (m, 4H), 0.94 (t, 6H) ppm.