Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: OCCOCCCl
Solvent: ClC(Cl)Cl
Product: ClCCOCCOC1CCCCO1
Temperature: 40 °C
Reaction time: 0.03 h
Yield: 101.2 %

Procedure:
In a drybox, 2-(2-chloroethoxy)ethanol (50.0 g, 0.401 moles) and 135 mL chloroform were added to a 500 mL 3-necked flask equipped with a stir bar, addition funnel and septum. 3,4-Dihydro-2H-pyran (39.7 g, 0.472 moles) in 35 mL chloroform was added dropwise over 30 min using an addition funnel. At the end of the addition, the flask was warm. The addition funnel was removed from the flask and replaced with a stopper, and the flask was transferred to the hood and placed under an atmosphere of nitrogen. Twelve drops of concentrated HCl were added dropwise via syringe. The septum was then replaced with a water condenser. The reaction was heated at 40° C. for 1 hr, and then allowed to cool to room temperature. The flask was opened to the air, 9 g of K2CO3 were added to the reaction mixture, and the mixture was stirred for two min before filtering. The solvent was removed via rotary evaporation, and the product was dried under vacuum for 8 hr at room temperature to give 84 g (0.406 moles) of 2[2-(2-chloroethoxy)ethoxyl]-tetrahydropyran.
Reaction SMILES: CCCC([C:6]1[C:7](=[O:17])[O:8][CH:9]=[C:10](CC(C)C)[C:11]=1[OH:12])=O.O[C:19]1[CH:24]=C(CC(C)C)O[C:21](=O)[CH:20]=1.[K+].[Br-]>>[OH:12][C:11]1[CH:10]=[C:9]([CH2:24][CH2:19][CH2:20][CH3:21])[O:8][C:7](=[O:17])[CH:6]=1
Reactant: CC(C)Cc1cc(O)cc(=O)o1
Reactant: CCCC(=O)c1c(O)c(CC(C)C)coc1=O
Agent: [Br-]
Agent: [K+]
Product: CCCCc1cc(O)cc(=O)o1

Procedure:
Proceeding in a similar manner as described in Section D of this example, 3-(3-methylpropionyl)-4-hydroxy-5-isobutyl-2-pyrone was converted to 4-hydroxy-6-isobutyl-2-pyrone. M.p. 110°-111° C., IR (KBr): 3300-2700, 1705, 1680-1660, 1585 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[C:16](Cl)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cnn2c(-c3ccccc3)nc3ccccc3c12
Yield: 43.1 %

Procedure:
20.4 g (0.1 mole) of 5-(o-aminophenyl)-4-nitropyrazole are dissolved in 200 ml of pyridine. To the solution obtained, 14.0 g (0.1 mole) of benzoyl chloride are added, drop by drop, and the temperature of the reaction mixture is increased by 10° to 15° C., spontaneously. The mixture is reacted for 2 hours, then poured into water, and the product that solidifies is filtered off and recrystallized from dichloroethane. Thus, 12.5 g (43%) of 1-nitro-5-phenylpyrazolo[1,5-c]quinazoline are obtained. M.p.: 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:25][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(CN4CCCC4)cc3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (75 mg) was dissolved in DCM (5 mL). Pyrrolidine (19 μl) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (160 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, overnight. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (59.2 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH:32]2[CH2:34][CH2:33]2)([CH3:31])[CH3:30])[NH:6]1)=[O:4].[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([CH:9]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH:32]3[CH2:33][CH2:34]3)([CH3:31])[CH3:30])[NH:6][CH:5]2[C:3]([OH:4])=[O:2])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1NC(CC(C)(C)C2CC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 99b (0.95 g, 1.87 mmol) in tetrahydrofuran (40 mL) was added an aqueous solution (20 mL) of NaOH (0.15 g, 3.7 mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 18 h. The “pH” of the mixture was adjusted to 5 by aqueous HCl solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated, and trituated with dichloromethane and hexanes to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid as a white solid (0.78 g, 80%)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:12][CH2:13][S:14][CH2:15][C:16]([OH:18])=O)=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16](=[O:18])[CH2:15][S:14][CH2:13][CH2:12][C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCNCC
Reactant: CCc1cc2c(cc1CCSCC(=O)O)OCO2
Product: CCc1cc2c(cc1CCSCC(=O)N(CC)CC)OCO2
Yield: 87.1 %

Procedure:
2.1 g of the title compound was prepared from 2.0 g of [{2-(6-ethyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid by using 2.7 g of diethylamine as a pale yellow oil according to the same procedure as that described in Example 32.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[N:16]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: N#CCBr
Reactant: c1cc(N2CCNCC2)ccn1
Product: N#CCN1CCN(c2ccncc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-4-yl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=202.2: 1HNMR(DMSO-d6) 8.15 (d, 2H), 6.80 (d, 2H), 3.80 (s, 1H), 3.35 (t, 4H), 2.50 (t, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]C(=O)C)[CH2:3][CH2:2]1.[OH-].[K+].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14]([CH3:21])([S:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)SC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCOCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
A solution of 153 g (0.96 mol) of thioacetic acid S-(tetrahydro-pyran-4-yl)ester in ethanol (3.5 L) is degassed with nitrogen over 0.5 h and 125 g (2.23 mol) of KOH are added. Then a solution of 250 mL (1.68 mol) of ethyl α-bromoisobutyrate in EtOH (1 L) are added over 0.5 h, during which the temperature is increased to 40° C. The reaction is stirred for 18 h at room temperature under a nitrogen atmosphere. The reaction mixture is filtered, the solid is washed with ethanol (0.5 L) and the filtrate is concentrated under reduced pressure. The crude material is dryloaded onto silica and purified by dry-flash column chromatography (silica, eluent: n-heptanes, 2-10% ethyl acetate) to afford 158 g of 2-methyl-2-(tetrahydro-pyran-4-ylsulfanyl)-propionic acid ethyl ester as an orange-brown oil. Yield: 71%; ES-MS: m/z 233 [M+H]; 1H-NMR
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCCCl)cc[n+]([O-])c1C

Procedure:
1.0 ml of thionyl chloride was gradually added to a solution of 0.92 g (5 mmol) of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide in 10 ml of chloroform under cooling with ice. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 100 ml of methyl ethyl ketone twice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvnet: chloroform/methanol=19:1) to obtain 0.56 g of 4-(2-chloroethoxy)-2,3-dimethylpyridine N-oxide as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]#[N:28])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:30]([O-])=O.[Na+]>O1CCOCC1.O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:4]=[C:3]([C:27]#[N:28])[C:2]3[N:1]=[N:30][N:8]([CH3:9])[C:7]=3[CH:6]=2)=[CH:11][C:12]=1[C:23]([F:26])([F:24])[F:25]
Reactant: CNc1cc(-c2ccc(OCOCCOC)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3-amino-6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (100 mg) was suspended in dioxane (1500 μl) and water (1500 μl) and cooled to 0° C. Hydrochloric acid (2M, 189 μl) followed by dropwise addition of sodium nitrite (25 mg) in water (500 μl) and the mixture stirred at room temperature for 2 hours. The suspension was filtered and the solid washed with water to afford pale brown solid 6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (92% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([OH:33])=[C:28](B(O)O)[CH:29]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:33])=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:25]=1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: OB(O)c1cc(F)ccc1O
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(F)ccc4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(5-Fluoro-2-hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 5-fluoro-2-hydroxyphenylboronic acid in 50% yield using method F; δH [2H6]-DMSO 13.09,(1H, b), 12.63,(1H, b), 8.36,(2H, m), 8.22,(4H, m), 7.99,(1H, d), 7.64,(1H, s), 7.22,(1H, t), 7.05-6.91,(3H, m), 3.80,(3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC)=[O:24])[CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:12]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(C(=O)O)CC2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.2 %

Procedure:
128 mg of ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylate (Example 83) was dissolved in 3 ml of ethanol, 0.28 ml of 12% sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature for 6 hours. Ethanol was distilled off and then the obtained residue was diluted with water and the aqueous layer was washed with diethyl ether. The aqueous layer was neutralized with a 10% hydrochloric acid to pH 7 and subjected to extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was washed with diethyl ether, and filtered and dried under reduced pressure to obtain 58 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[OH-].[CH2:17]([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CI>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:17]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1O
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6.0 g of 5-(tert-butyl)-2-hydroxybenzoic acid methyl ester in a round bottom flask was added tetrabutyl-ammoniumhydroxide 40% solution (7.45 g, 1 eq). The resulting solution was stirred at room temperature for 2 hr. All water was evaporated under reduced pressure and then in vacuo. To remove trace water, the salt was dried in a vacuum oven overnight and yielded 12.9 g (99%). To a solution of 12.9 g of tetra-butylammonium salt in 50 ml dry THF was slowly added methyliodide (3.61 mL, 2 eq). The resulting solution was stirred at room temperature for 2 hr. After the reaction was completed, the product was filtered out using ammonium iodide salt and washed with ethylacetate twice. The pH was adjusted to pH=2–3 using 1M HCl solution. This organic layer was collected by extraction with ethylacetate and water three times. The organic layer was dried over anhydrous magnesium sulfate (MgSO4). The organic layer was evaporated and the residue was purified by column chromatography (ethylacetate:hexane=1:5) (yield: 3.8 g, 60.0%) 1H NMR (CDCl3, 300 MHz): δ 1.30 (s, 9H), 3.86 (s, 3H), 3.90 (s, 3H), 6.90 (d, J=10.5 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.82 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C1C[O:34][CH2:33]C1.CO>[OH-].[Na+]>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][C:6]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[O:34][CH3:33])(=[O:21])=[O:22])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1S(=O)(=O)C1(C(=O)O)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g (40%); tan solid; mp 215° C.; MS: 469.7 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C.O>[ClH:34].[CH3:30][O:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][O:13][CH2:12][CH2:11][N:7]2[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2cccc(OC)c2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(C(=COCCN2CCC=C(C(=O)O)C2)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
1-(2-((2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (1.15 g, 0.0027 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (15 ml) and 12 N sodium hydroxide solution (0.5 ml) was introduced. After stirring the solution at room temperature for 4 h, ice (30 g) was added, and pH of the reaction mixture was adjusted to ca. 7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) was added, and the pH was further adjusted to ca. 1 with 37% hydrochloric acid solution. Water was added until the solid material was dissolved, and the dichloromethane phase was dried (Na2SO4) and evaporated to an oil, which was co-evaporated three times with acetone. The residue was triturated with diethyl ether to give the title compound (0.60 g, 52%).
Reaction SMILES: [N+:1]([C:4]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[OH-].[NH4+:17]>>[NH2:17][C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:9]=[C:10]([F:15])[C:11]=1[F:14])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1c(F)c(F)cc(C(=O)O)c1[N+](=O)[O-]

Procedure:
1.4 g (6.3 mmol) of 2-nitro-3,4,5-trifluoro-benzoic acid was treated with ammonium hydroxide to produce 3-amino-4,5-difluoro-2-nitro-benzoic acid. LCMS: 219 (M+1)+. 1.2 g (5.5 mmol) of 3-amino-4,5-difluoro-2-nitro-benzoic acid was heated with excess 21% NaOEt in ethanol at 90° C. for 6 h to yield 3-amino-5-ethoxy-4-fluoro-2-nitro-benzoic acid. LCMS: 245 (M+1)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[C:17]1([C:23]2[N:24]=[CH:25][C:26]([NH:29][C:30](=O)[O:31]C3C=CC=CC=3)=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:30]([NH:29][C:26]3[CH:25]=[N:24][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:28][N:27]=3)=[O:31])[CH2:3][CH2:4]2)[O:8]1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (6.24 g, 26.6 mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (7.59 g, 26.0 mmol) and triethylamine (18 mL, 180 mmol) in chloroform (200 mL) was stirred at 80° C. for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (100 mL). After the organic layer was washed with 10% citric acid aqueous solution (100 mL), 1N aqueous sodium hydroxide (100 mL) and then saturated saline solution (100 mL), the organic layer was dried over anhydrous Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=½) to provide the subject compound as a colorless solid. The solid was washed with diethyl ether (30 mL) to provide the subject compound (8.23 g) as a crude crystal. The crystal was dissolved in hot ethyl acetate (300 mL). After removal of about 100 mL of ethyl acetate by distillation, the white suspension began to occur. At this point the distillation was stopped and the whole was cooled and then kept at room temperature for 14 hours. The colorless prisms formed was collected by filtration, which was washed with heptane (20 mL). The obtained crystal was dried at 50° C. in vacuo for 6 hours to provide the subject compound (Crystal Form A) (5.17 g) as colorless prisms (melting point 210-211° C.).
Reaction SMILES: [CH2:1]([CH:5]1C(=O)O[C:8](C)([CH3:12])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].C([OH:17])C>>[O:17]=[C:1]([CH2:2][CH2:3][CH3:4])[CH2:5][C:6]([O:7][CH2:8][CH3:12])=[O:14]
Reactant: CCCCC1C(=O)OC(C)(C)OC1=O
Reactant: CCO
Product: CCCC(=O)CC(=O)OCC
Yield: 72 %

Procedure:
The 5-butyl-2,2-dimethyl-1,3-dioxane-4,6-dione thus obtained was allowed to reflux in ethanol for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=8/2) to obtain the ethyl 3-oxohexanoate shown by the formula below.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4](Cl)[N:3]=1.[Na].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Nc1nc(N)c(Br)c(Cl)n1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Nc1nc(N)c(Br)c(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-5-bromo-6-chloropyrimidine ( Phillips et. al., J. Org. Chem., 29, 1488-1490 (1963)) (2.3 g, 10 mmol) was added to a solution of sodium(0.29 g, 12.5 mmol) in benzyl alcohol ( 10 mL) under argon. The solution was heated in a 130° C. oil bath for 3 h and the benzyl alcohol was evaporated under reduced pressure to give a white solid. This solid was washed with water, and air dried. Crystallization from 50% aqueous ethanol gave white crystalline needles of 3f: yield, 2.32 g (76%); mp 165-166 ° C. (lit. 136° C.; Kosary et. al., Acta Pharm. Hung., 49, 241-247 (1989)); UV (pH 1) λmax236 nm (ε=0.873×104), 291 (1.388×104O); (pH 6.9) 236 (0.850×104), 277 (0.835×104); (pH 13) 234 (0.869×104), 277 (0.827×104 ); 1H NMR δ 5.30 (s, 2 H, ArCH2), 6.15 (s, 2 H, NH2, exchange with D2O), 6.32 (s, 2 H, NH2, exchange with D2O), 7.31-7.45 (m, 5 H, ArH); MS (EI) calcd. m/z for C11H11N4O79Br 294.0115, found 294.0127; calcd. m/z for C11H11N4O81Br 296.0094, found 296.0083; Anal. (C11H11N4OBr) C, H, N.