Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[Li]CCCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(O)(=O)C>C1COCC1>[CH3:7][CH2:6][C:3]([NH:2][CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][O:5][C:24]([C:23]1[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:25]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCC(CO)(NC)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(NC)c1ccccc1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
To a solution of 1.84 g of 8 (10.3 mmol) in 28 mL of anhydrous THF were added dropwise, at −78° C., 4.11 mL of n-BuLi (2.5 mol/L in hexanes). After 15 minutes, a solution of 2.31 g (10.01 mmol) of 3,4,5-trimethoxybenzoyl chloride in 15.8 mL of anhydrous THF was added. The reaction mixture was then allowed to warm to −30° C. (ca 1 h) and 19 mL of acetic acid were cautiously added. Solvents were removed under vacuum and 55 mL of diethyl ether and 55 mL of water were added to the previously obtained oil. After stirring until complete dissolution, the resulting mixture was then decanted and the aqueous layer alcalinized completely with solid Na2CO3 and re-extracted with diethyl ether. The organic layers were washed twice with a saturated aqueous solution of sodium carbonate and with brine and then dried over sodium sulphate. Diethyl ether was evaporated under vacuum and the ester 9 was purified by chromatography on silica gel column (ethyl acetate/n-hexane, 7:3) to give 1.4 g of pure N-desmethyltrimebutine 9 (49% yield) as a yellow pale oil. MS(ESI), m/e 374.1 (M+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18]([CH2:19][CH:20]=[CH:21][CH:22]=3)=[CH:17][NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.O.[H][H]>[Pd].CO>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16][C:15]1=[O:24]
Reactant: [H][H]
Reactant: O=C1NC=C2CC=CC=C2N1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NCc2ccccc2N1C1CCNCC1
Temperature: 40 °C
Yield: 44.3 %

Procedure:
In this reference example, 16.0 g of 1-benzyl-4-[3,5-dihydro-2(1H)-quinazolinon-1-yl]-piperidine, 4.0 g of 10% Pd-C, 50 ml of 1 N hydrochloric acid, 150 ml of water and 300 ml of methanol are mixed and stirred at 40° C. Hydrogen gas is introduced to the mixture for 5 hours with stirring. Then, the Pd-C is removed by filtration and the filtrate is concentrated. The white crystalline residue is dissolved in 50 ml of water. The solution is adjusted to pH 10 with aqueous 5 N sodium hydroxide and extracted with chloroform. The extract is washed with water, dried and thereafter concentrated. Then, 50 ml of a mixture of ethyl acetate and n-hexane (1:1 by volume) is added to the residue. After trituration, the solid is separated by filtration, washed with the same mixed solvent to obtain 9.9 g of a crude product. The crude product is recrystallized from water-ethanol to obtain 5.1 g of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[OH-].[Na+].[CH:24](O)=[O:25]>C(OC(=O)C)(=O)C>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:25]
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=CNCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88 %

Procedure:
Step 1): To a cooled solution (0°-5° C.) of 4-aminometyl-1-diphenylmethylpiperidine (3.0 g, 0.01 mol) in formic acid (7.5 ml), acetic anhydride (6 ml) was added and the reaction mixture was stirred at room temperature for 17 hours. An aqueous NaOH solution was added to adjust the mixture to pH 12 and the mixture was extracted with ether. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was recrystallized (diisopropyl ether) to give 4-(N-formylamino)methyl-1-diphenylmethylpiperidine (2.9 g, 88%); mp 125° C.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)(O)=[O:2].Cl.[CH3:36][NH:37][CH3:38].P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O.O>[CH3:36][N:37]([CH3:38])[C:1]([CH2:4][O:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:22][CH:23]=2)[CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: CNC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)O)c3ccccc32)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N(C)C)c3ccccc32)cc1
Reaction time: 2 h
Yield: 85.8 %

Procedure:
5-Carboxymethoxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) is dissolved in dimethylformamide (20 ml) and thereto are added dimethylamine hydrochloride (0.20 g) and diethyl chlorophosphate (0.33 g). To the mixture is added triethylamine (1.0 ml) under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes, and at room temperature for more 2 hours. Water is added to the reaction solution and the precipitated crystal is collected by filtration and recrystallized from ethyl acetate/n-hexane to give 5-dimethylaminocarbonylmethoxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) as colorless prisms, m.p. 203-204° C.
Reaction SMILES: [N+:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[CH:9]([CH:11]=[CH2:12])=[O:10].[H-].[Na+]>O1CCCC1>[N+:1]([C:4]1([CH2:12][CH2:11][CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C1CCCC1
Reactant: C=CC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCCC1([N+](=O)[O-])CCCC1

Procedure:
Condense nitrocyclopentane (prepared from bromocyclopentane and sodium nitrite) and acrolein in tetrahydrofuran in the presence of sodium hydride to obtain 3-(1-nitrocyclopentyl)propionaldehyde. Treat this aldehyde with p-toluenesulfonic acid in methanol and isolate 3-(1-nitrocylopentyl) propionaldehyde dimethyl acetal. Hydrogenate this compound with Raney nickel. Isolate 3-(1-aminocyclopentyl)propionaldehyde dimethylacetal and dissolve in aqueous acetone in the presence of p-toluenesulfonic acid and heat under reflux, followed by addition of toluene and azeotrope the mixture to give 1-azaspiro[4.4]-Δ1 -nonane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:12]([OH:14])[CH3:13].[ClH:15]>C1(C)C=CC=CC=1>[ClH:15].[CH2:12]([O:14][C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:11])[CH3:10])[CH:4]=1)=[NH:2])[CH3:13]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: CCO
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=N)c1cccc(C(C)=O)c1
Temperature: 0 °C

Procedure:
To an ice-water cooled solution of 29 g. (0.2 mole) of m-cyanoacetophenone in 375 ml. of dry toluene, containing 13 ml. (0.2 mole) of absolute ethanol, is bubbled a stream of hydrogen chloride gas for 2 hours. The solution is allowed to stand in a cold room overnight. The precipitate which forms is collected to give 34 g. of product. A small amount is recrystallized from ethanol (petroleum ether is added to initiate precipitation) to afford a sample with a melting point of 130°-132°.
Reaction SMILES: C[Si]([CH:5]([S:8][CH3:9])[S:6][CH3:7])(C)C.CCCCCC.C([Li])CCC.[CH:21]1[CH:26]=[CH:25][C:24]([C:27]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=O)=[CH:23][CH:22]=1.[Cl-].[Na+]>O1CCCC1>[CH3:7][S:6][C:5]([S:8][CH3:9])=[C:25]([C:24]1[CH:23]=[CH:22][C:30]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:29][CH:27]=1)[CH2:26][CH3:21]
Reactant: CSC(SC)[Si](C)(C)C
Reactant: O=C(CCOc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=C(SC)SC)c1ccc(Oc2ccccc2)cc1
Temperature: -73 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Trimethylsilyl-bis(methylthio)methane, 2.65 g, was dissolved in 15 ml of tetrahydrofuran and 7 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow under ice cooling. The mixture was stirred at the same temperature for 30 minutes. After cooling to -73° C., a solution of 2.26 g of 4-phenoxypropiophenone in 5 ml of tetrahydrofuran was dropwise added to the mixture. Then, the temperature was gradually elevated to room temperature followed by stirring for 16 hours. After saturated sodium chloride aqueous solution was added to the mixture, it was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 3.04 g of the oily product.
Reaction SMILES: [CH:1]([C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:2].[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[OH:2][CH2:1][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C=O)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1(CO)CCCC1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of methyl 1-formylcyclopentanecarboxylate (954 mg, 6.11 mmol, Synthesis 1997, 32-34) in ethanol (10 mL) was added sodium tetrahydroborate (104 mg, 2.75 mmol) at ambient temperature. After being stirred for 30 min, the mixture was concentrated in vacuo to give an oil. The residual oil was dissolved with ethyl acetate, and the solution was washed with brine. The extract was dried over magnesium sulfate and concentrated in vacuo to afford 806 mg (83%) of the title compound as a colorless oil. The crude product was used in the next step without further purification.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].I[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].O>CN(C)P(N(C)C)(N(C)C)=O.CCOCC>[O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:17])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(NCCCOc2ccccc2)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(OCC(O)CO)c1ccc(NCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 5.5 g of 4-(3-phenoxypropylamino)benzoic acid, 4.80 g of 25% aqueous sodium hydroxide, and 12.6 g of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(3-phenoxypropylamino)benzoate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Cl)[CH:6]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][C:24]1=[NH:32]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][C:24]2=[NH:32])[CH:6]=1)[CH3:2]
Reactant: N=c1[nH]c2ccccc2[nH]1
Reactant: CCOC(=O)c1cccc(OCCCCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCCCn2c(=N)[nH]c3ccccc32)c1
Temperature: 50 °C
Yield: 69.7 %

Procedure:
To a solution of 3-(3-chloro-propoxy)-benzoic acid ethyl ester (5.50 g, 22.7 mmol) in DMF (150 ml) at rt was added Cs2CO3 (14.8 g, 45.5 mmol) and 1,3-dihydro-benzoimidazol-2-ylidene amine (2.75 g, 20.7 mmol). The reaction was heated to 50° C. for 12 h. After this time, the resulting mixture was cooled to rt and partitioned between EtOAc and H2O. The organic layer was separated and the aqueous phase was extracted with additional EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated under redcued pressure. The crude product was purified by chromatography on silica eluting with 2% MeOH/dichloromethane to give 3-[3-(2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (4.9 g g, 64%). HPLC-MS 340 [M+1]+.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(#N)C>[N:11]1([CH2:2][O:3][C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: ClCOc1ccc(Cl)cc1
Solvent: CC#N
Product: Clc1ccc(OCn2cncn2)cc1
Temperature: 25 °C

Procedure:
α-Chloro-p-chloroanisole (10.6 g) and 1,2,4-triazole (12.4 g) in acetonitrile (120 ml) were refluxed for 48 hours. After cooling to room temperature, triazole hydrochloride was filtered off and acetonitrile removed at reduced pressure to give a sticky gum which was extracted with hot petroleum ether (80°-100°) and allowed to cool slowly to give colourless prisms of the title compound.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[N:8]1)([CH3:6])[C:3]([NH2:5])=[O:4]>C(O)C.[C].[Pd]>[NH2:12][C:10]1[CH:9]=[N:8][N:7]([C:2]([CH3:6])([CH3:1])[C:3]([NH2:5])=[O:4])[CH:11]=1
Reactant: CC(C)(C(N)=O)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C(N)=O)n1cc(N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
To a solution of 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanamide (1.0 g) obtained in Step B of Example 109 in ethanol (50 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature for 5 hr under hydrogen atmosphere (at normal pressure). The palladium carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethyl acetate/hexane) to give the title compound (760 mg).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>CC(N(C)C)=O>[N:21]1([C:2]2[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Reactant: C1CNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16), in DMA was treated with a large excess of azetidine (˜30 eq). The resultant solution was warmed to 100° C. and stirred at that temperature for 18 h. The reaction solution was cooled to rt, poured into 1N NaOH solution and then extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate gradient (MeOH—CH3CN (1:7)/CH2Cl2) to give 2-(5-(azetidin-1-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine, I-23, as a white solid (88% yield).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:12][NH:11][CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(C2CNCC(c3nc(C4CC4)no3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
185 mg (0.41 mmol) of the compound from Example 174A were initially charged in 25 ml of dichloromethane and, at RT, reacted with 0.32 ml (466 mg, 4.08 mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 126 mg (87% of theory)
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[O:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10].C(Br)C#C>C1COCC1.C1(C)C=CC=CC=1.[Cl-].[Na+].O.O>[CH2:3]([O:10][CH2:9][CH2:8][O:7][CH2:11][CH2:12][OH:13])[C:2]#[CH:1]
Reactant: OCCOCCO
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCOCCOCCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
To a stirred suspension of potassium tert-butoxide (1.06 g, 9.42 mmol) in THF (300 mL) cooled to 0° C. in an ice-bath was added a solution of 2,2′-oxydiethanol (4.60 g, 78.0 mmol) in THF (10 mL). The mixture was stirred at 0° C. for 30 min and was then allowed to warm to RT and was treated dropwise with propargyl bromide (1.68 mL of an 80% solution in toluene, 11.30 mmol). The reaction mixture was stirred at RT for 16 hr and diluted with brine and water (5:1, 50 mL) and was extracted with EtOAc (3×500 mL). The combined organic extracts were dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 25 to 60% EtOAc in heptane, to afford the title compound (10) (410 mg, 30%) as a yellow oil: 1H NMR (250 MHz, CDCl3) δ: 2.22 (1H, s), 2.45 (1H, t), 3.58-3.66 (2H, m), 3.67-3.79 (6H, m), 4.22 (2H, d).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][OH:8].[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C1(C)C(C)=CC=CC=1>[OH:8][CH2:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[N:1]1[C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]2[C:9]1=[O:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@@H]1CCC[C@@H]1CO
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H]1CO
Yield: 79.9 %

Procedure:
A mixture of (±) cis 1-amino-2-hydroxymethylcyclopentane (0.59 g, 5.1 mmol) and phthalic anhydride (0.76 g, 5.1 mmol) in xylene (40 ml) was heated under argon at reflux using a condenser fitted with a Dean and Stark trap. After 1.5 h the reaction was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with diethyl ether to give the title compound as a pale yellow oil (1.0 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[N:25](COCC[Si](C)(C)C)[C:24]4[C:23](=[O:34])[N:22]([CH2:35][CH2:36][CH3:37])[C:21](=[O:38])[N:20]([CH2:39][CH2:40][CH3:41])[C:19]=4[N:18]=3)[CH:14]=[N:13]2)[CH:6]=[CH:7][CH:8]=1>C(O)C.Cl.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[NH:25][C:24]4[C:23](=[O:34])[N:22]([CH2:35][CH2:36][CH3:37])[C:21](=[O:38])[N:20]([CH2:39][CH2:40][CH3:41])[C:19]=4[N:18]=3)[CH:14]=[N:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(CO)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC#Cc4cccc(CO)c4)c3)nc2n(CCC)c1=O
Yield: 51.7 %

Procedure:
To a solution of 8-{1-[3-(3-hydroxymethyl-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (25 mg) in ethanol (3 ml), aq. HCl (2 N, 1 ml) was added and the reaction mixture was refluxed for 2 hrs. The volatiles were evaporated and the residue obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4 and concentrated under vacuum. The residue obtained was purified by column to obtain 8-{1-[3-(3-hydroxymethyl-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (10 mg, 52%) as white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([C:14]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([C:27]2[C:28]([CH3:38])=[C:29]([F:37])[C:30]([C:33](OC)=[O:34])=[N:31][CH:32]=2)[CH:21]=3)=[O:15])[CH2:13][CH2:12]1>C(Cl)Cl>[F:37][C:29]1[C:28]([CH3:38])=[C:27]([C:22]2[CH:21]=[C:20]3[C:25]([CH:26]=[C:17]([NH:16][C:14]([CH:11]4[CH2:13][CH2:12]4)=[O:15])[N:18]=[CH:19]3)=[CH:24][CH:23]=2)[CH:32]=[N:31][C:30]=1[CH2:33][OH:34]
Reactant: COC(=O)c1ncc(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c(C)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)cnc(CO)c1F
Temperature: -15 °C
Reaction time: 1 h
Yield: 2.4 %

Procedure:
Diisobutylaluminum hydride (1.0M solution in tetrahydrofuran, 0.73 mL) was added dropwise to a solution of methyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-3-fluoro-4-methylpicolinate (60 mg, 1.8 mmol) in methylene chloride (1.5 mL) cooled at −15° C. After 1 hour at this temperature, the reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution (3 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid solution in water (20 mL). The organic layer was separated, and the aqueous layer was neutralized via addition of solid sodium bicarbonate solution and then extracted with ethyl acetate (50 mL). The combined organic portions were dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (15 mg, 23%). 1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 9.21 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 5.31 (s, 1H), 4.65 (s, 2H), 2.26 (s, 3H), 2.12-2.04 (m, 1H), 0.91-0.80 (m, 4H). LCMS (Method G): RT=7.53 min, M+H+=352.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][S:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]2)[CH2:15][CH2:14]1.[CH:26]1([CH:29]=[O:30])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[C:21]2([C:24]#[N:25])[CH2:22][CH2:23][CH:18]([S:17][CH2:16][CH:13]3[CH2:14][CH2:15]3)[CH2:19][CH2:20]2)[CH2:28][CH2:27]1
Reactant: N#CC1CCC(SCC2CC2)CC1
Reactant: O=CC1CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC1(C(O)C2CC2)CCC(SCC2CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirred solution of diisopropylamine (1.59 ml; 11.3 mmol) in THF (10 ml) at 0° C. was added dropwise butyl lithium (2.5 M in hexanes; 4.51 ml; 11.3 mmol). The mixture was stirred at 0° C. for 15 minutes then cooled to −78° C. A solution of 4-cyclopropylmethylsulfanyl-cyclohexanecarbonitrile (2 g; 10.2 mmol) in THF (10 ml) was added dropwise. On complete addition, the mixture was stirred at −78° C. for 30 minutes. Cyclopropanecarboxaldehyde (0.91 ml; 12.2 mmol) was added dropwise and the mixture was allowed to warm slowly to room temperature and stir for 64 hours. The mixture was quenched with brine (50 ml) and extracted with EtOAc (2×75 ml). The combined organics were washed with saturated sodium hydrogen carbonate solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give an orange oil. The crude product was chromatographed on silica eluted with 25-30% EtOAc in hexane to give the product as an orange oil (1.9339 g). 1H NMR (400 MHz, DMSO): δ 5.29 (1H, d, J 4.9), 2.76 (1H, dd, J 4.9, 7.8), 2.68-2.58 (1H, m), 2.15-2.11 (1H, m), 2.04-1.98 (4H, m), 1.56-1.38 (4H, m), 0.98-0.88 (2H, m), 0.52-0.48 (3H, m), 0.45-0.37 (1H, m), 0.34-0.28 (2H, m), 0.19-0.17 (2H, m). m/z=266 (M+H+).