Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]3[C:37](=[O:38])[CH2:36][C:35]([CH3:39])=[N:34]3)=[CH:32][C:27]=2[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>Cl>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]3[C:37](=[O:38])[C:36](=[N:20][NH:2][C:3]4[C:4]([OH:19])=[C:5]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=5)[CH:6]=[C:7]([CH3:9])[CH:8]=4)[C:35]([CH3:39])=[N:34]3)=[CH:32][C:27]=2[CH2:26][CH2:25]1
Reactant: CC1=NN(c2ccc3c(c2)CCO3)C(=O)C1
Reactant: O=N[O-]
Reactant: Cc1cc(N)c(O)c(-c2cccc(C(=O)O)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NN(c2ccc3c(c2)CCO3)C(=O)C1=NNc1cc(C)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
3′-Amino-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid hydrochloride 11f (287 mg, 1.03 mmol) was dissolved in 3.5 mL of hydrochloric acid (1 N) upon cooling by an ice-water bath, followed by dropwise addition of 1.5 mL of aqueous sodium nitrite (78 mg, 1.13 mmol). After the mixture was stirred for 20 minutes, 2-(2,3-dihydro-benzofuran-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 7c (200 mg, 0.93 mmol) was added. The mixture was adjusted to pH 8-9 by batch addition of aqueous sodium bicarbonate (1.298 g, 15.45 mmol). The generated bubbles were quenched with 2 mL of ethanol. The mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and then the filter cake was dissolved in 20 mL of water. After mixing well, the mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid, filtered and dried. The residue was washed with 10 mL of the solvent mixture of dichloromethane/methanol (V:V=1:1), and then the crude product was purified by HPLC to obtain the title compound 3′-{N′-[1-(2,3-dihydro-benzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid 13 (100 mg, yield 23.0%) as a red solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9]C(OC)=O)=[C:6]([O:16][CH2:17][C:18]([O:20]CC)=O)[CH:5]=1)[CH:2]=[CH2:3].[H-].[Na+].Cl>O1CCCC1>[CH2:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH2:9][C:18](=[O:20])[CH2:17][O:16][C:6]=2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OCC(=O)OC)c(OCC(=O)OCC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCc1ccc2c(c1)OCC(=O)CO2
Temperature: 0 °C
Yield: 41.9 %

Procedure:
A solution of 69.0 g (234 mmol) of methyl 4-allyl-2-(ethoxycarbonylmethoxy)phenoxyacetate was added dropwise in the course of 2.5 h to a suspension of 12.0 g (500 mmol) of sodium hydride in 500 ml of tetrahydrofuran. The reaction mixture was then refluxed for 20 h and, after cooling, poured into 1.5 l of ice water. The resultant mixture was acidified to pH 2 with 2N hydrochloric acid and extracted three times, each time with 2 l of ether. The combined ether extracts were dried over sodium sulfate, freed from solvent on a rotary evaporator and taken up into 400 ml of ethanol. 400 ml of 2N hydrochloric acid were added and the mixture was refluxed for 20 h. The mixture was then poured into 1.5 l of ice water, the product was extracted four times, each time with 1.5 l of ether, and the combined ether extracts were washed with 1 l of water and 100 ml of saturated sodium chloride solution. After drying over sodium sulfate, concentration on a rotary evaporator and flash chromatography. (pentane/ether, 4:1, Rf=0.37) on silica gel, 20.0 g (42%) of 7-allylbenzo[b][1,4]dioxepin-3-one (1) were obtained as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[CH:13](O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.S(Cl)([Cl:19])=O>CCOCC>[ClH:19].[ClH:19].[Cl:19][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[C:8]1=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC1C(=Cc2cccnc2)N2CCC1CC2
Solvent: CCOCC
Product: Cl
Product: ClC1C(=Cc2cccnc2)N2CCC1CC2
Temperature: 0 °C

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (3 g, 140 mmol) was dissolved in 200 ml methanol and sodium borohydride (3 g, 79.6 mmol) was added in portions (exothermic reaction) with vigorous stirring. After 1 hr of continued stirring, acetone (100 ml) was slowly added to neutralize the remaining borohydride reagent. The mixture was evaporated to dryness and the resulting residue suspended in water (200 ml) and extracted three times with 200 ml portions of chloroform. The chloroform phases were combined, dried over MgSO4, and rotary evaporated to give a clear oil; crystallization of the free base gave a quantitative yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a white precipitate. 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7 mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol) stirred under a nitrogen atmosphere at 0° C., the reaction was than brought to room temperature and stirred for one additional hour. Rotary evaporation at 60° C. produced a viscous oil which when suspended in ether afforded 3-chloro-2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). The chloroquinuclidine (0.3 g, 1.3 mmol) was combined with 50 ml ethanol in a hydrogenation vessel, then wet Raney nickel (2.5 grams) was added in one portion. Hydrogenation (50 psig) was carried out for 6 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave the desired 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a white reside which easily recrystallized from ethanol-ether to give a white crystalline solid (0.21 g 70%).
Reaction SMILES: [C:1]([O:4]CC[CH2:7][CH2:8][O:9][C:10](=O)[CH3:11])(=[O:3])[CH3:2].C(OC(OC(=O)C)CCC)(=O)C>>[O:9]1[CH2:8][CH2:7][CH2:11][CH2:10]1.[C:1]([OH:4])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCOC(C)=O
Agent: CCCC(OC(C)=O)OC(C)=O
Product: C1CCOC1
Product: CC(=O)O
Yield: 90 %
Yield: 93 %

Procedure:
The tube reactor, charged with 110 grams of alumina catalyst (1/8 pellets, Harshaw A1-0104T), is maintained at 250° C while 25.0 grams of 1,4-butanediol diacetate and 50 ml. of water are admitted to the evaporator simultaneously from different addition funnels over a 20 minute period. The aqueous effluent collected contains tetrahydrofuran, acetic acid, and about 10% of the original diacetate. The mixture is again taken through the tube. The effluent from this second pass contains, as found by quantitative glpc analysis, 0.3 grams of residual butanediol diacetate (1% unconverted), 9.2 grams of tetrahydrofuran (90% yield), and 15.9 grams of acetic acid (93% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:18][CH2:17][C:12]2([O:16]CCO2)[CH2:11][CH2:10]1.FC(F)(F)C([O-])=O>CCCCCC.CCOCC>[C:9]12([CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]1)[C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][O:19]2
Reactant: OCc1ccccc1C1(O)CCC2(CC1)OCCO2
Agent: O=C([O-])C(F)(F)F
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1CCC2(CC1)OCc1ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
0.64 g (2.62 mmol) of 8-(2-Hydroxymethyl-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol was added to 80% trifluoroacetate (TFA) 2.5 ml. The mixture was stirred at room temperature for 5 hours. Rotory evaporation of the TFA left thick brown oil. The oil was dissolved in 2.0 ml of EtOAc and washed first with 1N NaOH and then with H2O. The organic layer was dried with MgSO4 and concentrated, leaving a thick yellow oil. Hexane/ether (2:1) was added and the sides of the flask were scratched. A precipitate began to form. 0.23 Grams of 3′H-Spiro[cyclohexane-1,1′-isobenzofuran]-4-one were obtained, 44% yield.
Reaction SMILES: [CH:1]1([NH:6][C:7](=S)[NH:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[ClH:11].[CH:1]1([NH:6][C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([CH3:20])[NH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=S)NC1CCCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(NC2CCCC2)n[nH]c1C
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
A stirred slurry of 8.3 g (0.052 mole) of 4-cyclopentyl-3-thiosemicarbazide in 50 mL of absolute ethanol under nitrogen atmosphere was treated with 8.6 g (0.052 mole) of ethyl 2-chloroacetoacetate. The reaction mixture which, after filtering, turned pale yellow, as stirred for 18 hr at ambient temperature, treated with 20 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1 hr. The reaction mixture was filtered hot and the filtrate concentrated in vacuo to a yellow-orange solid. Most of the solid was dissolved in 100 mL of hot absolute ethanol. The mixture was filtered, and when the filtrate was treated with dipropyl ether (150 mL) a precipitate formed which was collected by filtration to give 11.7 g of crude product. Recrystallization from benzene/ligroin with charcoal treatment gave 7.6 g of fine white fluffy needles, mp 175°-177° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[N:20]=[C:19]([O:21][C@H:22]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:23]32[CH2:25][CH2:24]3)[CH:18]=[N:17][CH:16]=1)([CH3:5])C.[C:37](O)(C(F)(F)F)=O>CO.C(Cl)Cl>[CH2:25]1[C:23]2([CH2:26][CH2:27][NH:28][CH2:29][C@@H:22]2[O:21][C:19]2[N:20]=[C:15]([C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([CH:3]([CH3:5])[CH2:2][OH:1])[CH:7]=4)[N:11]([CH3:37])[N:10]=3)[CH:16]=[N:17][CH:18]=2)[CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3n[nH]c4ccc(C(C)(C)CO)cc34)n2)C1
Solvent: ClCCl
Solvent: CO
Product: CC(CO)c1ccc2c(c1)c(-c1cncc(O[C@H]3CNCCC34CC4)n1)nn2C
Yield: 52.8 %

Procedure:
A solution of (R)-tert-butyl 4-((6-(5-(1-hydroxy-2-methylpropan-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (18 mg, 0.036 mmol) in TFA (41.6 mg, 0.365 mmol) was stirred at RT for 30 min. The mixture was concentrated and was dissolved in MeOH (˜20 mg/ml) and injected (1×1.000 ml) onto the Shimadzu preparatory LC (Protocol B) before the pure fraction was concentrated via rotary evaporation to give impure product. A preparatory TLC plate was loaded with the crude mixture and run 2 times in 20% MeOH/DCM; scraping the plate, extraction with MeOH, filtration, and concentration via rotary evaporation afforded 2-(3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-1-methyl-1H-indazol-5-yl)-1-propanol (7.6 mg, 0.019 mmol, 53.0% yield) as a beige solid. MS (ESI, pos. ion) m/z: 394.0 (M+1).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][C:8]3[N:9]2[C:12]([CH3:15])=[N:13][N:14]=3)=[CH:4][CH:3]=1.[SH:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][C:12]1[N:9]2[C:10]3[C:5]([C:6]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][C:8]2=[N:14][N:13]=1)=[CH:4][CH:3]=[C:2]([S:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1)[CH:11]=3
Reactant: Cc1nnc2cc(-c3ccccc3)c3ccc(I)cc3n12
Reactant: OC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2cc(-c3ccccc3)c3ccc(Sc4cccc(C5(O)CCOCC5)c4)cc3n12
Temperature: 70 °C

Procedure:
5u (100 mg, 0.26 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-ol (5v, 65 mg, 0.31 mmol), iPr2NEt (0.1 mL, 0.52 mmol), Pd2dba3 (6 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01 mmol) were dissolved in 1,4-dioxane (4 mL) and degassed with N2 for 5 minutes. The mixture was heated to 70° C. until no starting material was seen by tlc analysis. The reaction was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography to give the desired product, 5y.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:10][CH3:11])=[N:5][O:6][C:7]=1[CH2:8][CH3:9].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[CH2:10]([C:4]1[C:3]([CH2:2][S:19][C:17]2[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=2)=[C:7]([CH2:8][CH3:9])[O:6][N:5]=1)[CH3:11]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1noc(CC)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1noc(CC)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-diethyl-1,2-oxazole (4.6 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (440 mg, 3.3 mmol), and triethylamine (1.3 mL, 9.3 mmol) in absolute ethanol (35 mL) was stirred at room temperature overnight. The mixture was evaporated. The residue was treated with water (50 mL). The solid material was removed by filtration. The solid was washed with diethyl ether (3×25 mL). The filtrate was recovered, extracted with water (2×75 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording the title compound (220 mg, 30% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.18 (m, 6H), 2.21 (s, 3H), 2.65 (m, 2H), 2.83 (m, 2H), 4.22 (s, 2H), 6.02 (s, 1H); M+ 280.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[CH:23]([N:26]([CH:40]([CH3:42])[CH3:41])[CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=O)=[CH:32][C:31]=1[F:39])([CH3:25])[CH3:24].C(N(C(C)C)CCOC1C=C[C:53]([CH2:54][NH:55][C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=CC=1F)(C)C>>[CH:23]([N:26]([CH:40]([CH3:42])[CH3:41])[CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][N:55]([CH2:54][CH3:53])[C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[CH:32][C:31]=1[F:39])([CH3:25])[CH3:24]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN(C(C)C)C(C)C)c(F)c1)C2
Reactant: CC(C)N(CCOc1ccc(C(=O)O)cc1F)C(C)C
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN(C(C)C)C(C)C)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 4-(2-diisopropylaminoethoxy)-3-fluorobenzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-diisopropylaminoethoxy)-3-fluorobenzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (459 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-diisopropylaminoethoxy)-3-fluorobenzyl]ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (429 mg). This compound (427 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (303 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd]>[F:19][C:17]([F:18])([F:20])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]2[CH:3]=[CH:2][N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)[CH:12]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)n3nccc3n2)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: FC(F)(F)c1cccc(-c2ccn3nccc3n2)c1

Procedure:
The mixture of 1.65 g. 7-chloro-5-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine, 0.46 g. of anhydrous sodium acetate, 0.20 g. of 10% palladium on charcoal catayst and 100 ml. of absolute alcohol is hydrogenated in a Parr apparatus beginning at 10 lbs. pressure until one equivalent of hydrogen is absorbed in about 40 minutes. The catalyst is removed by filtration and the solvent is evaporated to dryness and water is added. The solid is collected by filtration and is recrystallized from methylene chloride-hexane to yield the desired material, m.p. 117°-118° C.
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(O)CCCC1>C1(C)C=CC=CC=1>[C:1]([O:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC(=O)CCCCC
Agent: OC1CCCC1
Solvent: Cc1ccccc1
Product: CCCCCC(=O)OC1CCCC1
Yield: 70 %

Procedure:
Likewise, refluxing a toluene solution containing one equivalent of hexyl hexanoate, 2 equivalents of cyclohexanol and 1 mol % of the PNN complex 1 under argon atmosphere for 20 h resulted in 84% conversion of hexyl hexanoate as determined by GC analysis, with the exclusive formation of the ester cyclohexyl hexanoate in 83% yield (Table 8, entry 2). Notably, unlike the traditional transesterification methods, this reaction does not form an alcohol product; rather, an irreversible incorporation of both the acyl and alkoxo parts of the starting ester into the product ester takes place. While 2 equivalents of the alcohol with respect to the ester are sufficient, somewhat higher yields are obtained when 3 equivalents of alcohol were used. Thus, reaction of 3 equivalents of cyclohexanol with hexyl hexanoate resulted after 26 h in 96% conversion with 95% yield of cyclohexyl hexanoate, as observed by GC, and confirmed by GC-MS by comparison with an authentic sample (Table 8, entry 3). The pure product was isolated by evaporation of the solvent followed by passing through a basic alumina plug and analysis by NMR and GC-MS. Use of the PNP complexes 2 or 3 resulted after 20 h in 58% or 17% yield of cyclohexyl hexanoate, respectively. Studying the scope of this new reaction with regard to the secondary alcohol, reaction of hexyl hexanoate with cyclopentanol in the presence of 1 mol % 1 was carried out. After 26 h reflux in toluene, cyclopentyl hexanoate (70% yield) was formed, with 71% conversion of hexyl hexanoate (Table 8, entry 4). Similarly, upon reaction of hexyl hexanoate with excess of 1-phenylethanol, 50% conversion of hexyl hexanoate with the formation of 49% of the acylated product was observed (Table 8, entry 5). The lower conversion of the ester is a result of facile dehydrogenation of 1-phenylethanol to acetophenone (49%). Because of the expected easy dehydrogenation of the isopropyl alcohol to acetone, transesterification with this alcohol was performed in a closed vessel, to retard this dehydrogenation process. Thus, heating hexyl hexanoate with excess of isopropyl alcohol resulted after 19 h in 83% conversion of hexyl hexanoate with the formation of isopropyl hexanoate in 67% yield (entry 6). The reaction of hexyl hexanoate and 3-pentanol led to 91% conversion of the ester with formation of 3-pentyl hexanoate in 90% yield after 26 h reflux (entry 7).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:15]1[C:16]([NH:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][OH:40])=[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]>C1COCC1>[CH3:8][S:9]([O:40][CH2:39][C:30]1[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])=[N:32][C:33]2[N:24]([C:22](=[O:23])[NH:21][C:18]3[CH:17]=[C:16]([NH:41][CH2:42][CH2:43][O:44][CH3:45])[C:15]([C:13]#[N:14])=[CH:20][N:19]=3)[CH2:25][CH2:26][CH2:27][C:28]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CO)c(C(OC)OC)nc32)ncc1C#N
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (120 μL, 0.866 mmol) and methanesulfonyl chloride (57 μL, 0.731 mmol) were added to solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 171, 300 mg, 0.657 mmol) in THF (11 ml) at 0° C. The reaction mixture was stirred for approximately 2.5 h at 0° C. and filtered to remove solid impurities. The solid residue was washed with THF and the filtrate was concentrated to yield the title compound as beige solid which was used directly in the next step. (UPLC-MS) ESI-MS 535.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.67 (br s, 1H), 8.24 (s, 1H), 7.67 (s, 1H), 7.55 (s, 1H), 5.47 (s, 3H), 5.33 (br s, 1H), 4.08-4.00 (m, 2H), 3.63 (t, 2H), 3.53-3.45 (m, 8H), 3.41 (s, 3H), 3.07 (s, 3H), 2.88 (t, 2H), 2.09-1.94 (m, 2H).
Reaction SMILES: C([Li])C[CH2:3][CH3:4].[CH2:6]([OH:10])[CH2:7][C:8]#[CH:9].[CH2:11]([Si:13](Cl)([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]>CCCCCC.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:11]([Si:13]([C:8]([Si:13]([CH2:3][CH3:4])([CH2:14][CH3:15])[CH2:11][CH3:12])([CH3:9])[C:7]#[C:6][OH:10])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]
Reactant: C#CCCO
Reactant: [Li]CCCC
Reactant: CC[Si](Cl)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)C(C)(C#CO)[Si](CC)(CC)CC
Temperature: -30 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
n-Butyl lithium (776 ml of a 2.5M solution in hexane, 1.94 mol) was added over a 2 h period to a stirred solution of 3-butyn-1-ol (68 g, 0.97 mol), in anhydrous THF (1.16 l), at -30° C. The mixture was stirred at -30° C. for 1 h (dianion precipitates out) and triethylsilyl chloride (300 g, 1.99 mol) was then added dropwise, ensuring that the temperature remained below -20° C. The solution was stirred at -10° C. for 1 h and then at room temperature for 1 h. Hexane (1.36 l) and Na2CO3 solution (7.0 g in 700 ml of H2O) were added to the reaction mixture, at -10° C., and the layers separated. The aqueous layer was extracted with hexane and the combined extracts were washed with water, dried (Na2SO4) and evaporated to give the title-bis triethylsilyl butynol (289 g, 100%), δ (250 MHz, CDCl3) 0.80-0.94 (12H, m, 6 of SiCH2CH3), 1.22-1.32 (18H, m, 6 of SiCH2CH3), 2.76 (2H, t, J=7.3Hz, CH2), 4.00 (2H, t, J=7.3Hz, CH2).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[Cl:16].[OH:17][S:18](O)(=[O:20])=[O:19].O=S(=O)=O>O>[Cl:15][C:4]1[C:3]([Cl:16])=[C:2]([Cl:1])[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[C:5]=1[S:18]([OH:20])(=[O:19])=[O:17]
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)c(Cl)c2[nH]1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=S(=O)(O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C
Yield: 92 %

Procedure:
4,5,6-trichloro-2-trifluoromethylbenzimidazole (145 parts) was added gradually to stirred oleum (1260 parts) and the mixture then refluxed for 2 hours. After cooling, the mixture was poured into water (3000 parts), the temperature being allowed to rise to near boiling. The mixture was cooled to room temperature overnight and the crystalline product was filtered off, washed with water and dried to give 165.9 parts (92% yield) of 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonic acid.