Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:17].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:27])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(CCO)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To the solution of 1-chloro-4-[(4-ethenylphenyl)oxy]-2-methylbenzene (2.46 g, 10.05 mmol) in dry THF (30 mL), was added 9-BBN (30.2 mL, 15.08 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (3 mL), followed by aq. NaOH (13.00 mL, 39.0 mmol), and 30% H2O2 (13.00 mL, 126 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.13 g, 42.8% yield) as colorless oil. LCMS: rt=3.49 min, [M+H+]=245
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:29][O:28]2)=[CH:23][N:22]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:29][CH:27]([C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=3)[OH:28])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: Cc1ccc(C2CO2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C)nc2)CCN2CCCC12
Reaction time: 0.08 h

Procedure:
To a solution of 9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (200 mg, 0.88 mmol) in DMF (10 mL) was added sodium hydride (96 mg, 2.6 mmol). After stirring for 5 min, a solution of 2-methyl-5-oxiranyl-pyridine (175 mg, 1.3 mmol) in DMF (1 mL) was added dropwise into the reaction mixture, which was stirred at RT for 5 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-(6-methyl-pyridin-3-yl)-ethanol. The product was further purified by chiral HPLC separation to give enantiomers 198a and 198b. Enantiomers 198c and 198d are also obtained by this method. 1H NMR, (CDCl3, freebase) δ (ppm): 8.45 (s, 1H), 7.6 (dd, 1H), 7.22 (m, 2H), 7.1 (t, 1H), 7.05 (t, 1H), 5.08 (q, 1H), 4.8 (dt, 1H), 3.5 (m, 2H), 3.4 (m, 2H), 3.1 (d, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.6 (m, 2H), 2.5 (s, 3H), 2.41 (s, 3H), 2.1 (m, 3H).
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].C([Sn](CCCC)(CCCC)[C:39]1[O:40][CH:41]=[CH:42][CH:43]=1)CCC.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccco3)cc2)CC1

Procedure:
A mixture of intermediate (29) (0.0036 mol), tributyl-2-furanyl-stannane (0.029 mol), PdCl2(PPh3)2 (0.0007 mol) and Na2CO3 (0.0576 mol) in dioxane (30 ml) was stirred and refluxed for 1 hour. Water was addedd. The mixture was extracted with ethyl acetate. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:cyclohexane/ethyl acetate 80/20). The pure fractions were collected and the solvent was evaporated, yielding 4-[4-[[2-(2-furanyl)benzoyl]amino]phenyl]-α-phenyl-1-piperazineacetic acid, methyl ester (intermediate 30, mp. 90° C.).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][C:20](=O)[NH:21]4)=[N:16][CH:15]=3)[CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:14]([N:12]3[CH2:13][CH:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)[CH2:11]3)=[CH:15][N:16]=2)[N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)N1CCN(C2CN(c3cnc4ccc(=O)[nH]c4c3)C2)CC1
Product: CC(C)N1CCN(C2CN(c3cnc4ccc(Cl)nc4c3)C2)CC1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-9) (5.346 g, 16.3 mmol, 1.0 eq) was dissolved in POCl3 (100 mL) and the resulting mixture was stirred at reflux for 30 min. The reaction was complete based on TLC analysis. Then the mixture was cooled to RT and concentrated in vacuo to remove POCl3. The residue was poured into ice water (500 mL) and neutralized with saturated aqueous Na2CO3 solution to adjust the pH value to 8-9 while keeping the temperature below 0° C. The mixture was stirred at RT for 30 min. The residue was extracted with DCM (4×200 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-7% MeOH-DCM) to afford the desired product 2-chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridine (C-10) (1.9 g, 33.7% yield). ESI-MS m/z: 346.14 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[N:11]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]3[N:20]=[N:21][N:22]=[C:14]3[C:13]=2[N:23]=1)[CH3:9]>ClCCl>[CH2:8]([C:10]1[N:11]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH2:29])[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]3[N:20]=[N:21][N:22]=[C:14]3[C:13]=2[N:23]=1)[CH3:9]
Reactant: CCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCCN
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A solution of trifluoroacetic acid (188 mL, 2.44 mol) in dichloromethane (300 mL) was cooled to 0° C. A solution of tert-butyl 2-{2-[(8-ethyl-5,6-dimethyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)]ethoxy}ethylcarbamate (19.7 g, 48.8 mmol) in dichloromethane (300 mL) was then slowly added over a period of 30 minutes, and the reaction was stirred overnight. The volatiles were removed under reduced pressure, and the residual brown oil was stirred with 2-propanol (300 mL) to form a white salt, which was isolated by filtration and dried in a vacuum at 80° C. The salt was dissolved in water (200 mL), and solid sodium carbonate was added to adjust to pH 12. The solution was extracted with chloroform overnight with a continuous extractor. The extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.5 g of 2-[2-(8-ethyl-5,6-dimethyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)ethoxy]ethylamine as a white solid, m. p. 181–183° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:15]O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([O:10][CH3:15])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1O
Reactant: CO
Product: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a nitrogen inlet, and a condenser were added 10.0 g of 3-tert-butyl-4-hydroxybenzoic acid (ICN Biomedicals. Inc., Aurora, Ohio 44202), and 200 mL of MeOH. The solution was acidified by bubbling HCl gas through for 5 min. and was then heated at reflux for 5h. The solution was cooled to RT and concentrated in vacuo to dryness. The resulting solid was dissolved in EtOAc. The solution was washed three times with 5% aqueous NaHCO3, dried over anhydrous MgSO4 and concentrated to dryness to afford 9.65 g (90%) of methyl 3-tert-butyl-4-bydroxybenzoate as a white crystalline solid, m.p. 144-145° C.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH3:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][C:1]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:6][CH3:5])=[O:15])=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC(=O)Cl)cc1

Procedure:
A 20% solution of phosgene (170 mL, 0.33 mol) in toluene was added to a 500 mL pear-shaped flask (flame-dried, N2). To the flask was added methyl-p-hydroxybenzoate (42.6 g, 0.28 mol) with stirring. Through an addition funnel was added pyridine (26.7 mL, 0.33 mol) in toluene while the reaction mixture was cooled in an ice bath so that the temperature did not exceed 20° C. The solution turned a yellowish color during the addition. The reaction mixture was stirred for 3 h, at which point the mixture was filtered on a buchner funnel. The pyridinium salts were washed with toluene (150 mL) and the combined organic phase washed with 1 N HCl (2×), water (2×), dried over CaCI2 and Na2SO4, and the toluene removed in vacuo to yield yellowish crystals. After continued drying, the product (38 g, 63%) turned a greyish color. m.p. 52-53° C. (lit. 51-52° C.).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH2:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][OH:38])[C@@H:21]1[OH:39])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40]I>>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH2:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][O:38][CH3:40])[C@@H:21]1[OH:39])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OCCO)[C@@H]1O)(c1ccccc1)c1ccccc1
Reactant: CI
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cnc2c(N)ncnc21

Procedure:
5′-O-t-Butyldiphenylsilyl-2′-O-(hydroxyethyl)-adenosine is treated with methyliodide as per the procedure of Example 24 to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]([OH:14])=O)=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:7]2[C:8]3[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=3[CH:4]=[CH:5][CH:6]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1CCCC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3=O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (430 mg, 2.26 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (464 mg, 2.26 mmol), HATU (1 g, 2.70 mmol) in anhydrous DMF (20 mL) is added DIPEA (446 μL, 2.70 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (65) as white solid (828 mg, 97%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(O)C>N1C=CC=CC=1>[CH2:16]([O:18][N:19]=[C:4]1[C:3]2[C:8](=[C:9]([CH3:13])[CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1)[CH3:17]
Reactant: CCON
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCON=C1CCSc2c(C)cc(Br)c(C)c21
Yield: 92.6 %

Procedure:
3.0 Grams (11 mmol) of 5,8-dimethyl-6-bromothiochroman-4-one and 2.2 g (22 mmol) of O-ethylhydroxylamine hydrochloride were refluxed under heat in a mixed solvent containing 10 ml of ethanol and 10 ml of pyridine for 30 minutes. The solvents were distilled off under reduced pressure, and then the residue was treated with 5% hydrochloric acid and extracted with ethyl acetate. The so-obtained solution was consecutively washed with 5% aqueous potassium carbonate and with saturated sodium chloride solution and dried over sodium sulfate. The solvent was distilled off to give 3.2 g of 4-ethoxyimino-5,8-dimethyl-6-bromothiochroman (yield 92%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].Cl.[NH2:9][OH:10].N1C=CC=CC=1>CCO>[OH:10][NH:9][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[NH:7]
Reactant: NO
Reactant: N#Cc1nccs1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N=C(NO)c1nccs1

Procedure:
To a solution of thiazole-2-carbonitrile (0.42 g, 3.80 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.53 g, 7.60 mmol) and pyridine (0.27 g, 3.40 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step (crude yield 0.50 g, 91% crude yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]([O-])(=[O:17])C.[NH4+].C(O)=O>O>[CH:15]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1c(N)sc2c1CCC2
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1c(NC=O)sc2c1CCC2
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of compound 2g [Compound of Formula 2 wherein R1=COOEt, R2, R3=(CH2)3] (10.0 g, 0.046 mol), ammonium acetate (3.64 g, 0.060 mol) and formic acid (35.74 mL, 0.946 mol) was stirred at 130-135° C. for 8 h. It was then cooled to room temperature and diluted with water (150 mL), extracted with ethyl acetate (3×100 mL), dried over Na2SO4, concentrated and purified by column chromatography to give pure compound of Formula (3g); 10.66 g; Yield: 97%; 1H NMR (200 MHz, CDCl3+DMSO-d6): δ 0.1.33 (t, J=8 Hz, 3H), 2.25-2.43 (m, 2H), 2.74-2.89 (m, 4H), 4.26 (q, J=8 Hz, 2H), 8.48 (s, 1H) 11.16 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][N:24]=2)=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:16])[CH2:29][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[N:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccnc(-c2ccncc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccnc(-c2ccncc2)n1)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-methylaminomethylpiperidine-1-carboxylic acid tert-butyl ester (37 mg, 0.16 mmol) in anhydrous CH2Cl2 (3 mL) was added 2-pyridin-4-yl-pyrimidine-4-carbaldehyde (Preparation 2, 30 mg, 0.16 mmol) followed by NaBH(OAc)3 (38 mg, 0.18 mmol). The mixture was stirred vigorously at rt for 24 h, before being partitioned between CH2Cl2 (30 mL) and H2O (20 mL). The aqueous phase was extracted with CH2Cl2 (20 mL), then the combined organics were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (EtOAc) gave the title compound. RT=2.36 min; m/z (ES+)=398 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3nnnc23)CC1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3nnnc23)CC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 69.5 %

Procedure:
A 1 L round bottom flask was charged with tert-butyl 4-(5-bromotetrazolo[1,5-a]pyrazin-8-yl)piperazine-1-carboxylate (50 g, 0.13 mol), thiophene-2-boronic acid (22 g, 0.17 mol), tetrakis(triphenylphosphine)palladium(0) (7.5 g, 6.5 mmol), Cs2CO3 (51 g, 0.16 mol), 1,4-dioxane (600 mL) and H2O (240 mL). After the air was purged by bubbling N2 into the solution, the resulting solution was stirred at 80° C. under N2 for 10 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with CH2Cl2, and then crystallized from methanol, to afford 35 g (70%) of the product as a yellow solid. MS m/z: 388 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOP(=O)(CCCCCO)OCC
Solvent: c1ccncc1
Product: CCOP(=O)(CCCCCOS(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 0 °C

Procedure:
30 g (0.134 mol) of diethyl 5-hydroxypentylphosphonate (see Example 21) were dissolved in 200 ml of pyridine, and the solution was cooled to 0° C. and treated with stirring with 26.1 g (0.134 mol) of 4-toluenesulfonyl chloride. The reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed several times with 20% strength citric acid solution and water and dried over sodium sulfate. After evaporating the solvent, a pale yellow oil remained, which was employed without further purification.
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)#[N:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[CH2:2])#[N:7]
Reactant: N#Cc1cccc(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (75 g, 209.71 mmol) in dry THF (750 mL) at 0° C. under nitrogen was added dropwise n-BuLi (83 mL, 2.5 M in hexanes, 207.50 mmol). The mixture was warmed to room temperature. 3-Cyanobenzaldehyde (25 g, 190.65 mmol) was added as a solid in 5 g batches, and the mixture was stirred at room temperature overnight. The reaction was quenched in water, and the solvent was removed under vacuum. The residue was dissolved in the minimal amount of THF, and triphenylphosphine oxide was precipitated using ether. The solid was filtered through diatomaceous earth, and the filtrate was concentrated. Distillation by Kugelrhor at 90° C./33 Pa (0.25 mm Hg) gave the product as a colorless oil (15.5 g, 62%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27]C(=O)[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].C(O)C.O>>[NH2:25][C@@:24]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)[CH:15]=2)[CH:20]=1)([CH3:30])[CH2:28][OH:27]
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](c4ccccc4)CC3)ccc2c1
Yield: 41.3 %

Procedure:
The mixture of (R)-4-(6-(cis-4-phenyl-cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (160 mg, 0.00040 mol) and lithium hydroxide (100 mg, 0.0044 mol) in ethanol (4 mL, 0.08 mol) and water (0.9 mL, 0.05 mol) was heated to reflux overnight. LCMS showed reaction complete. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. The combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product. A final purification on Gilson HPLC 0.1% TFA-ACN/H2O to gave the product as a white solid (62.0 mg, 41% yield). LCMS 359.33 ([M-NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 1.71 (brd, J=13.1 Hz, 2 H), 1.78 (s, 3 H), 1.83 (brd, J=14.7 Hz, 2 H), 1.98 (dd, J=13.7, 11.1 Hz, 2 H), 2.24 (d, J=12.6 Hz, 2 H), 2.67 (dd, J=11.6, 11.5 Hz, 1H), 3.82 (d, J=11.7 Hz, 1H), 3.92 (d, J=11.7 Hz, 1H), 4.84 (brs, 1H), 7.16 (m, 1H), 7.27-7.32 (m, 6H), 7.52 (d, J=8.7 Hz, 1H), 7.85 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)c(OCc2ccc(F)cc2)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)c(OCc3ccc(F)cc3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.09 (2H, s), 5.16 (2H, s), 5.69 (1H, s), 6.98-7.13 (5H, m), 7.37-7.40 (3H, m), 7.56 (1H, s), 8.03 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C23H16F2N4O2, 419. Found, 419.