Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([OH:14])=[CH:11][CH:10]=[CH:9]2)[CH3:3].FC(F)(F)C(O)=O.[C:22]([O:25][CH2:26]C)(=O)C.O>O1CCCC1.N1C=CC=CC=1>[CH2:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([O:14][CH2:22][O:25][CH3:26])=[CH:11][CH:10]=[CH:9]2)[CH3:3]
Reactant: CC(O)c1cccc2cccc(O)c12
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc2cccc(OCOC)c12
Reaction time: 6 h

Procedure:
270 g of 8-(1-hydroxyethyl)-1-naphthol was dissolved in 500 ml of tetrahydrofuran and 170 ml of pyridine, followed by dropping 357 g of anhydrous trifluoroacetic acid under ice-cooling conditions in 45 minutes. The reaction solution was agitated under ice-cooling conditions for 0.5 hours, after which 2 liters of ethyl acetate was added. After washing with a saturated saline solution, 1N hydrochloric acid, a saturated saline solution and a sodium hydrogencarbonate saturated aqueous solution in this order, the reaction solution was dried with anhydrous magnesium sulfate. Insoluble matters were removed by filtration and 3.75 liters of tetrahydrofuran was added to the resultant filtrate. 37.5 g of 10% palladium-carbon (water content: 50%) was further added, followed by violent agitation in an atmosphere of hydrogen at 1 atm., for 6 hours. After removal of the palladium-carbon by filtration, the filtrate was concentrated to half in volume. The resultant residue was added under agitation to a saturated sodium hydrogencarbonate aqueous solution, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the resultant residue was dissolved in 1 liter of N,N-dimethylformamide. 69 g of 60% sodium hydride was gently added to the solution under ice-cooling conditions, followed by agitation for further 20 minutes. 160 g of chloromethyl methyl ether was dropped in the resultant reaction solution so that the inner temperature did not exceed 20 C. After further agitation at room temperature for 30 minutes, the reaction solution was poured into iced water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off, followed by purification by silica gel column chromatography (hexane), thereby obtaining 259 g of the captioned compound as a light yellow oily substance.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[C:19]=3[CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OC(C)(C)C)(=O)C>[C:5]([O:26][CH:20]([C:19]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][CH2:4][C:5]=2[CH:10]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:10])([CH3:6])[CH3:4]
Reactant: CCOC(=O)C(O)c1c(-c2ccc3c(c2)CCCO3)nc2ccccn12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)nc2ccccn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 124 %

Procedure:
To a solution of ethyl 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)imidazo[1,2-a]pyridin-3-yl]-2-hydroxyacetate (53 mg, 0.15 mmol) in tert-butyl acetate (4.6 mL) at −20° C. was added perchloric acid (0.6 mL). The mixture was stirred at 0° C. for 2 hours before being poured into a saturated aqueous solution of sodium bicarbonate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 60/40) to provide the desired product (19d) (38 mg, 0.093 mmol, 57%) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][N:19]3[C:15](=[O:25])[C:16]4[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:18]3=[O:20])=[CH:9][CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: OCc1ccc(N2CCOCC2)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a THF (200 mL) solution of (6-(morpholin-4-yl)pyridine-3-yl)methanol (CA 388088-73-1) (3.2 g), phthalimide (3.64 g) and triphenylphosphine (6.49 g), diisopropylazodicarboxylate (5.43 mL) was added at 0° C. for 5 minutes. The reaction solution was concentrated under reduced pressure after 12-hour stirring at room temperature. 3.8 g of the title compound was obtained by the residue was purified by silica gel chromatography (heptane-ethyl acetate system).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[O:1]([CH2:8][CH2:9][CH2:10][N:21]1[CH2:22][CH2:23][CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(OCCCN2CCC(c3ccccc3)CC2)cc1
Yield: 64.2 %

Procedure:
A mixture of 3-phenoxypropyl bromide (224 mg, 1.04 mmol), 4-phenylpiperidine (140 mg, 0.870 mmol) and K2CO3 (264 mg, 1.91 mmol) in 15 mL of EtOH was refluxed under N2 for 12 hr. The inorganic salt was removed through a short column of silica gel and washed with EtOAc (3×15 mL). The filtrate was evaporated in vacuo to give a residue, which was purified by flash chromatography giving the title as a pale yellow oil (165 mg, 64%): 1H NMR (CDCl3) 1.90 (m, 4 H), 2.10 (m, 4 H), 2.55 (m, 1H), 2.70 (bs, 2 H), 3.20 (bs, 2 H), 4.05 (m, 2 H), 6.92 (m, 4 H), 7.29 (m, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(Br)(Br)(Br)[Br:19].C(=O)=O.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CCOCC.C(O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([Br:19])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: O=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)[C@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (320 g, 1.30 mol) and carbon tetrabromide (540 g, 1.94 mol) in dichloromethane (3.2 L) at 0-5° C. (dry ice/dichloromethane bath) add triphenylphosphine (1.95 mol, 514 g) in portions over 30 min and stir at room temperature for 4 h. Add ethanol (3.2 L) and stir for an additional 2 h. Transfer the reaction to an 18 L carboy and add ether (8 L) until precipitation occurs. Stir the mixture overnight. Filter off the solids and concentrate the ether layer. Dissolve the oily residue in dichloromethane and filter through a silica plug eluting with dichloromethane until no more product can be detected by TLC. Concentrate the dichloromethane layer and treat with 5% ethyl acetate in hexanes (4 L) causing a white solid to form. Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes and collect only the fractions that contain the desired product. Concentrate the solution, dissolve in 5% ethyl acetate in hexanes (2 L) and purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes to obtain the title compound as a yellowish oil (372.4 g, 93%). [α]D20+53.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.33 and 1.39 (two s, 9H), 2.40 (m, 1H), 2.53 (m, 1H), 3.35 (m, 1H), 3.66 (s, 3H), 3.80 (m, 1H), 4.35 (q, 1H), 4.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[CH3:48][S:49]([O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:34]([F:35])[CH:33]=1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (3.8 g, 6.75 mmol) and DIPEA (3.52 mL, 20.3 mmol) in DCM (100 mL) at 0° C. was added methanesulfonyl chloride (603 μL, 7.8 mmol). After the reaction was slowly warmed to ambient temperature over 30 min, it was partitioned in DCM (100 mL) and water (100 mL). Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=1:3) to give 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (4.1 g, 95% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.25 Hz, 1H), 7.22 (s, 1H), 6.82-6.72 (m, 2H), 6.58-6.47 (m, 2H), 6.42-6.32 (m, 4H), 4.55 (dd, J=5.27, 3.62 Hz, 2H), 4.18 (dd, J=5.26, 3.64 Hz, 2H), 4.04 (s, 2H), 3.78 (s, 3H), 3.09 (s, 3H), 1.50 (d, J=10.49 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-bromo-3-pyridinamine (2 g, 11.56 mmol), triethylamine (6.6 mL, 47.39 mmol) in dichloromethane (40 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 15 min and then benzenesulfonyl chloride (3.21 mL, 23.69 mmol) was added slowly to give a brown solution. The reaction mixture was stirred for 2 h at room temperature. Diluted with dichloromethane and then washed with saturated aqueous sodium chloride solution, separated the organic layer, dried over sodium sulphate, concentrated under high vacuum, light yellow solid obtained. The solid was dissolved in methanol (20 mL), cooled to 0° C., added 10N aqueous sodium hydroxide (20 mL) solution. The reaction mixture was stirred for 1 h and then distilled out methanol completely, extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound MS (M+1): 315.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[OH:11][C:12]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][O:31][C:28]2[CH:27]=[CH:26][C:25]([C:12]3([OH:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:21])=[O:20])=[CH:30][CH:29]=2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(O)cc1
Reactant: Fc1cc(F)cc(CBr)c1
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCc2cc(F)cc(F)c2)cc1
Yield: 85 %

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in Example 48 from 3,5-difluorobenzyl bromide and [2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine to provide 511 mg as a brown oil. This material was purified via silica gel chromatography employing the Chromatotron® using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 4:1 to yield the title compound (360 mg, 85%) as a white solid. Ion spray M.S. 438.3 (M*−1). Calculated for C22H27NO4SF2: Theory: C 60.12, H 6.19, N 3.19. Found: C 59.32, H 6.14, N 3.26.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH:28]=[CH2:29].O>CN(C=O)C>[CH2:29]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12]1)[CH:28]=[CH2:27]
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and allyl iodide (23 μL, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 302.1, found 302.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.CC(C1C=CC(OC)=CC=1)=O.COC1C=CC([C@H](O)C)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)O)cc1
Agent: COc1ccc(C(C)=O)cc1
Agent: COc1ccc([C@@H](C)O)cc1
Product: COc1ccc([C@H](C)O)cc1
Reaction time: 168 h
Yield: 48 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized green pea protein for the substrate (±)-1-(4-methoxyphenyl)ethanol (200 mg) requires 7 days by going through bioconversion to 4-methoxyacetophenone accompanying sterically selective oxidation of (R)-1-(4-methoxyphenyl)ethanol to obtain 96 mg of (S)-1-(4-methoxyphenyl)ethanol at a yield of 48%. Optical purity was obtained at 95% e.e. Furthermore, HPLC conditions were set at a flow rate of 1.0 ml/min, while GC conditions were set to an oven temperature of 190° C.
Reaction SMILES: [B]1OC2C(=CC=CC=2)O1.[F:10][C:11]([F:28])([F:27])[C:12]([C:14]1[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[O:13].[OH-].[Na+].OO>C1COCC1>[F:28][C:11]([F:10])([F:27])[C@@H:12]([C:14]1[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[OH:13]
Reactant: Cc1ccc(C(=O)C(F)(F)F)c(-n2ccc(C)n2)n1
Agent: OO
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](O)C(F)(F)F)c(-n2ccc(C)n2)n1
Temperature: -70 °C
Reaction time: 12 h

Procedure:
A solution of (S)-(−)-2-Butyl-CBS-oxazaborolidine solution (3.0 ml 1.0 M in toluene) and catecholborane (30 ml 1.0 M in THF) was stirred at RT for 30 min. The mixture was then cooled to −70° C. and 2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone (1 g, 2.9 mmol) in THF (16 mL) was added dropwise. After addition, the reaction mixture was warmed up to −32° C. and stirred for 12 h. After this time, 3N NaOH (18 mL) was added followed by H2O2 (18 mL) and the temperature of the reaction mixture was increased to RT for 30 min and then extracted with ethyl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/hepate) to provide the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH2:15])[S:7][C:6]=2[CH:16]=1.F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[N+:25]([O-:27])=[O:26])[S:7][C:6]=2[CH:16]=1
Reactant: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(Br)ccc12
Yield: 77.7 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 6-bromo-2-aminobenzo[b]thiophene-3-carboxylate (8.8 g), 2,4-difluoronitrobenzene (5.6 g) and dimethyl sulfoxide (100 ml), ethyl 6-bromo-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (10 g) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:33])[C:12]2[C:7](=[C:8](OC(=O)CCCC)[CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.C[OH:43]>[OH-].[Na+]>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:33])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:43])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCC(=O)Oc1cccc2c(=O)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c(CCCC)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2ccc(O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 2-butyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-8-valeryloxy-4(3H)-quinazolinone (0.3 g) in methanol (5 ml) and 1N sodium hydroxide (2 ml) was stirred at room temperature for 1 hour. After addition of 1N hydrochloric acid, the reaction solution was extracted with ethyl acetate and the organic layer was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from ethyl acetate-ether gave colorless crystals (0.2 g, 80%), mp 212°-214° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][C:19](OCC)=[O:20])[NH:14][C:13]=2[CH:24]=1.C(=O)=O.[OH-].[Na+]>O1CCCC1.O.CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[NH:14][C:13]=2[CH:24]=1
Reactant: CCOC(=O)CC1COc2ccc(OC)cc2N1
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc2c(c1)NC(CCO)CO2
Reaction time: 1.5 h

Procedure:
130 ml of tetrahydrofuran are introduced into a 1 l reactor which is cooled with a mixture of ice and salt and, under an argon atmosphere, 5 g (0.132 mol) of lithium aluminium hydride are added, followed by dropwise addition of 20.73 g (0.0825 mol) of ethyl (±)-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-3-acetate dissolved in 130 ml of tetrahydrofuran, and the mixture is stirred for 1.5 h. The reactor is cooled with a mixture of cardice and acetone, 40 ml of water and 20 ml of 1N sodium hydroxide are added dropwise and stirring is continued for 0.5 h.
Reaction SMILES: C(O[C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)=O)C.Cl.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)(=[NH:19])[NH2:18].[OH-].[Na+]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:6]2[N:19]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:18]=[C:4]([OH:15])[CH:5]=2)[CH:13]=1
Reactant: N=C(N)c1ccccn1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(-c2cc(Cl)ccn2)nc(-c2ccccn2)n1
Reaction time: 7 h

Procedure:
13.15 g (58 mmol) of 3-(4-chloropyrid-2-yl)-3-oxopropionic acid ethyl ester are dissolved in 400 ml of ethanol, and 9.10 g (58 mmol) of 2-amidinopyridine hydrochloride are added. After the addition of 14.44 ml of 4N sodium hydroxide solution, refluxing is carried out for 7 hours. The mixture is cooled and concentrated to a fifth of its original volume. The crude product is filtered off and recrystallised from methanol, yielding 6-(4-chloropyrid-2-yl)-2-pyrid-2-yl-pyrimidin-4-ol in the form of beige needles.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[C:11](OC)([O:12]C)[CH2:10][CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1.O.C(O)(C(F)(F)F)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[F:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCCCF
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(=O)C(OCCCF)C1

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-(3-fluoropropoxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (127a) (2.27 g, 21.2 mmol), a water/TFA mixed solution (3/1, 12 mL) and di-tert-butyl dicarbonate (2.18 g, 10 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 1.71 of the title compound as a colorless oily substance (88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:9]2[C:10](=[O:14])[NH:11][CH2:12][CH2:13][N:8]2[N:7]=1)=[O:5])[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:9]2[C:10](=[O:14])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][CH2:13][N:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2n(n1)CCN(c1ccc(F)cc1)C2=O
Temperature: 130 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
Copper (I) iodide (0.18 g, 0.95 mmol) was added to a suspension of 4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (1.0 g, 4.78 mmol), 1-bromo-4-fluorobenzene (1.0 mL, 9.56 mmol), N,N′-dimethylethylenediamine (0.30 mL, 2.86 mmol) and K2CO3 (1.3 g, 9.56 mmol) in toluene (20 mL). The reaction mixture was stirred at 130° C. for 16 hours. The mixture was filtered through a pad of diatomaceous earth which was washed with AcOEt. The mixture was diluted with AcOEt and washed with a 16% aqueous solution of NH4OH. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(4-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (1.3 g, 90% yield) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20])=[O:5])C>CO.[OH-].[Na+]>[CH3:20][C:7]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:13])[CH:10]=[C:11]([CH3:12])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C)cc(=O)n(-c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(=O)n(-c2ccccc2)c(C)c1C(=O)O
Reaction time: 5 h
Yield: 53.8 %

Procedure:
A mixture of 2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (108 mg, 0.398 mmol) in methanol (0.8 mL) and 32% aq. NaOH (0.25 mL) was shaken at 60° for 22 hrs (after 5 hours only 70% conversion was observed). The reaction mixture was quenched with water (5 ml), extracted with ether (3×2 ml), and acidified 3M HCl (1 mL, pH=0). The title compound was separated by filtration to give 52.1 mg of colorless solid, yield 54%. LC-MS (m/z) 244.5 (MH+); tR=0.54. 1H NMR (600 MHz, DMSO-d6): 1.94 (s, 3H, 2-Me), 2.19 (d, J=0.9 Hz, 3H, 4-Me), 6.29 (s, 1H, 5-H), 7.25 (dm, J=7.7 Hz, J<1.5 Hz, 2H, two ortho-H of Ph), 7.47 (tt, J=7.4 Hz, J=1.2 Hz, 1H, para-H of Ph), 7.53 (tm, J=7.5 Hz, J<1.7 Hz, 2H, two meta-H of Ph), 13.26 (br. s, 1H, CO2H).