Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:28])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:28][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:35]1[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A vial was charged with tert-butyl 7-bromo-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.250 g, 0.518 mmol), 2-fluoropyridin-3-ylboronic acid (0.15 g, 1.04 mmol), potassium phosphate (0.33 g, 1.55 mmol) and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.018 g, 0.026 mmol). The vial was sealed before evacuating and backfilling with nitrogen. The solids were suspended in 1,4-dioxane (2.22 mL) and water (0.37 mL). The vial was placed in a pre-heated 100° C. oil bath. The reaction was stirred for 1 h before cooling to RT. The reaction was diluted with water (30 mL) and extracted with ether (2×50 mL). The combined organic layers were washed sequentially with water and brine before drying over sodium sulfate. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography to afford tert-butyl 3-chloro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.21 g, 0.43 mmol, 83% yield).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[C:17](C(O)=O)[S:18][C:12]=2[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl>[ClH:1].[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][S:18][C:12]=2[CH2:11][CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc2c(s1)CCN(Cc1ccccc1)CC2
Agent: Cl
Product: c1ccc(CN2CCc3ccsc3CC2)cc1

Procedure:
3.1 gm (0.096 mol) of 6-benzyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic acid hydrochloride were refluxed for 48 hours in 30 ml of concentrated hydrochloric acid. After cooling, the reaction mixture was concentrated by evaporation in vacuo, the residue was mixed with water, and the aqueous solution was made alkaline with 6 N sodium hydroxide solution and extracted several times with ether. The ether phases were again washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo. After evaporating again with benzene, a brown oil remained which was dissolved in isopropyl alcohol. The hydrochloride was precipitated with isopropanolic hydrochloric acid and then recrystallized from isopropyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:29][S-:30].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11][CH:10]2[CH2:23][S:30][CH3:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (200 mg) in DMF (3 ml) was added sodium thiomethoxide (46.3 mg), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (110 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[C:15](=O)([O:18]C)[O:16][CH3:17].[H-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH:11]([C:15]([O:16][CH3:17])=[O:18])[C:10]1=[O:14]
Reactant: COc1ccccc1C1CCCC1=O
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(c2ccccc2OC)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-methoxyphenyl)cyclopentanone (6.64 g, 34.9 mmol), dimethyl carbonate (58.8 ml, 698 mmol) and MeOH (4 drops) was stirred while sodium hydride (3.07 g, 60% wt, 77 mmol) was added slowly at 0° C. The mixture was warmed to RT and then heated to reflux for 2 hr and then stirred at RT overnight. The reaction was quenched with 1 N HCl (77 mL, 77 mmol) and extracted with ethyl acetate. The organic extracts were washed with water, dried with brine, and concentrated in vacuo. The crude product was purified by flash chromatography (SG, 0 to 75% EtOAc/Hexane) to get methyl 3-(2-methoxyphenyl)-2-oxocyclopentanecarboxylate (5.3 g, 21.35 mmol, 61.2% yield). LC-MS (M+Na)+=271.1. 1H NMR (500 MHz, CD3OD) δ 7.26-7.16 (m, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.92-6.84 (m, 2H), 3.73-3.69 (m, 3H), 3.68 (s, 3H), 3.60-3.49 (m, 1H), 3.49-3.40 (m, 1H), 2.40-2.31 (m, 1H), 2.31-2.17 (m, 2H), 2.16-2.01 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([CH3:34])[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[C:16]=2[NH:21][C:22]([O:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH3:26])=[O:23])=[CH:11][CH:10]=1)C.[OH-].[Li+]>CO.O>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:25]([O:24][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[N:18][O:19][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][CH2:6][C:5]([CH3:35])([CH3:34])[C:4]([OH:36])=[O:3])=[CH:14][CH:13]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(C)(C)CC#Cc1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(C#CCC(C)(C)C(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 5-(4-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-2,2-dimethyl-pent-4-ynoic acid ethyl ester (0.46 mmol) in MeOH and H2O was added lithium hydroxide, and the reaction was stirred at 60° C. overnight. The mixture was acidified and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. Mass spec. data (M+H)=481.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[C:34]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:16][CH:17]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(C2CCCCC2)sc2cc(O)ccc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCCCC3)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 mg of (6-hydroxy-2-cyclohexylbenzo[b]thien-3yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone is dissolved in 1 mL of pyridine, 0.1 mL of benzoyl chloride is added, and this mixture is agitated for one hour at room temperature. Ice is added to the reaction mixture, and the system is agitated for one hour. The organic layer is extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The solvent is distilled off, and the crude product thus obtained is refined by TLC (developing solvent was chloroform:methanol=9:1), which gives 37 mg of (6-benzoyloxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:22]I>CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19]([O:21][CH3:22])=[N:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: COCOc1cccc2oc(-c3n[nH]c(=O)o3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2oc(-c3nnc(OC)o3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.17 g) in DMF was added dropwise a solution (20 ml) of 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (1.0 g) obtained in Starting Material Synthesis Example 116 in DMF at room temperature, and the mixture was stirred for 30 min. Thereto was added methyl iodide (0.26 ml), and the mixture was further stirred for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure to give the title compound (0.80 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>C(O)C>[C:2]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][CH:5]=1)[O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CCOC(=O)CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cccc(OCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 5.0 g (36.7 mmol) of 3-hydroxyacetophenone, 8.18 g (36.7 mmol) of ethyl 6-bromohexanoate and 50 mL of ethanol. The clear reaction mixture was treated with potassium carbonate (6.03 g, 44.0 mmol) and heated to reflux. After stirring for 24 hr at reflux, the reaction mixture was cooled to 25° C., filtered through a Celite pad and concentrated. The residue was taken up in of ethanol and treated with 15 mL of 2N aqueous sodium hydroxide (30 mmol). The reaction mixture was stirred for 6 hr at 25° C., before the ethanol was stripped off. The residue was acidified with aqueous 1N hydrochloric acid. The resulting solid was isolated by filtration and purified by recrystallization from ethanol/water to yield an off-white solid, 7.57 g, mp 70-72° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]1([CH2:20][CH2:21][CH2:22]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:14]1([CH2:20][CH2:21][CH2:22][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (2.50 g) and 3-phenylpropan-1-ol (2.8 mL) in tetrahydrofuran (70 mL), triphenylphosphine (5.46 g) was added at room temperature. Next, diethyl azodicarboxylate (9.4 mL, 40% toluene solution) was added dropwise thereto, followed by stirring at room temperature for 2 hours. Then, the reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1 to 5:1) to give the title compound (3.02 g) having the following physical properties.
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[S:10][CH:11]=[C:12]([CH3:14])[CH:13]=1)(=[O:8])C>>[CH3:14][C:12]1[CH:13]=[C:9]([C:6]([OH:8])=[O:2])[S:10][CH:11]=1
Reactant: CC(=O)c1cc(C)cs1
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To an aqueous solution of sodium hypochlorite (available chlorine 5%) (92.6 mL, 143.0 mmol) at about 0° C. was added sodium hydroxide (1.14 g, 28.6 mmol) and the mixture was stirred at about 0° C. until all of the sodium hydroxide had dissolved. To this solution was added 2-acetyl-4-methylthiophene (2.0 g, 14.3 mmol) at about 0° C. After the addition was complete, the mixture was heated to about 70° C. for about 3 hours, then the solution was cooled and was carefully quenched by addition of a solution of sodium bisulfite (23 g) in water (150 mL). After stirring for about 20 minutes, the solution was acidified by addition of concentrated hydrochloric acid and the precipitate was collected by filtration and dried under high vacuum to provide the desired product. MS (DCI-NH3): m/z 160 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]([OH:14])=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].S(Cl)([Cl:17])=O>>[Cl:17][C:12](=[O:14])[CH2:11][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1(CC(=O)O)CCOCC1
Product: COC(=O)C1(CC(=O)Cl)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Thionyl chloride (20 mL) was added to [4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (970 mg, 4.80 mmol) and the solution was stirred at rt for 3 h. The solvent was then removed and mixture was azeotroped with dichloroethane three times to afford methyl 4-(2-chloro-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.05 g, 99%), which was used without purification in the next step.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:32])=[CH:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cnc3c(C(=O)O)cnn3c2C2CCCCC2)cc1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2cnc3c(C(=O)O)cnn3c2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a cloudy solution of 14 mg (0.038 mmol) of 7-cyclohexyl-6-(4-methylsulfanyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 2 mL of chloroform was added 9 mg (1.5 equiv) of m-chloroperoxybenzoic acid (mCPBA) and the cloudy solution became clear. Since after 5 min of stirring at rt TLC indicated disappearance of starting material, the mixture was concentrated to a residue which was purified via reverse-phase chromatography (using Gilson) to afford (after lyophilization) 10 mg (69% yield) of 7-cyclohexyl-6-(4-methanesulfinyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (491) as a solid as indicated by LC-MS—calcd for C20H21N3O3S [M++H]+: 384.13, found: 384.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH2:29][N:28]1[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39]>CN(C)C(=O)C>[CH3:35][N:34]([CH3:36])[C:33]([O:32][C@H:30]1[CH2:29][N:28]([C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39])[C@H:27]([CH2:26][CH2:25][O:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:31]1)=[O:37]
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCCl
Reactant: COc1cccc(CCc2ccccc2)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1c(CCc2ccccc2)cccc1OC
Yield: 99.4 %

Procedure:
670 mg of 6-methoxy-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 360 mg of potassium t-butoxide and 1000 mg of (2S,4R)-2-(2-chloroethyl)-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1500 mg (99% yield) of the title compound as an oily substance.
Reaction SMILES: [Cl:1][Si:2](Cl)([CH3:4])[CH3:3].[CH:6]1([NH-:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Li+].CCCCCC>C1COCC1>[Cl:1][Si:2]([CH3:4])([CH3:3])[NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[Si](C)(Cl)Cl
Reactant: [NH-]C1CCCCC1
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(Cl)NC1CCCCC1
Reaction time: 8 h
Yield: 84 %

Procedure:
In the drybox in a 250 mL flask 60.0 mL (490.89 mmol) of dichlorodimethylsilane was stirred in about 80 mL of THF. To this stirring solution 6.00 g (57.08 mmol) of lithium cyclohexylamide was added as a solid slowly and stirred overnight. The THF was removed under vacuum leaving a cloudy solution. Hexane was added to this mixture and the solids were filtered off and washed with hexane. The hexane was then removed from the filtrate under vacuum leaving a clear light yellow product weighing 9.18 g. Yield 84 percent.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]([S:24]([C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][N:31]=[CH:32]2)(=[O:26])=[O:25])[CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])=O)(C)(C)C.[ClH:37].CO>>[ClH:37].[CH:32]1[C:33]2[C:28](=[C:27]([S:24]([N:12]([CH2:13][CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10][CH2:9][NH2:8])(=[O:26])=[O:25])[CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1
Reactant: CC(C)(C)OC(=O)NCCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 9 (266 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (203 mg) as white powdery solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[C:10]([CH3:17])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:17])[CH3:16]
Reactant: CNC1CCN(Cc2ccccc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.15 g) and 1-benzyl-4-methylamino-3,3-dimethylpiperidine (0.5 g, 2.1 mmol) in methanol (10 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-methylamino-3,3-dimethyl-piperidine. Yield 0.3 g (99%), C8H18N2, m/z 143 (M+1), PMR (CDCl3): 0.88 (s, 6H), 1.24 (m, 2H), 1.8 (bs, 2H, D2O exchangeable), 1.8 (m, 1H), 2.1 (m, 1H), 2.4 (s, 3H), 2.6 (d, 2H), 2.86 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.Br[C:13](Br)([CH2:24][CH3:25])[C:14]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][CH3:21])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:11][O:10][C:8]([C:6]1[CH:7]=[C:2]([O:1][CH:13]([CH2:24][CH3:25])[C:14]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][CH3:21])=[O:15])[CH:3]=[N:4][CH:5]=1)=[O:9]
Reactant: CCC#CC(C)(C)NC(=O)C(Br)(Br)CC
Reactant: COC(=O)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C(=O)OC)c1
Temperature: 70 °C

Procedure:
3-Hydroxy-5-methoxycarbonylpyridine (1.68 g, prepared using the method described in Bull. Acad. Sci. (Chem. Div.), (1976), 598) and 2-bromobromo-N-(5-methylhex-3-yn-5-yl)-butyramide (3.06 g) were dissolved in dry N,N-dimethylformamide (30 ml) containing anhydrous potassium carbonate (2.35 g). The mixture was heated to 70° C. for 3 hours with stirring, cooled to ambient temperature, diluted with water and extracted with diethyl ether (three times). The organic extracts were combined, washed with water (three times), dried over magnesium sulphate and evaporated under reduced pressure to give a brown gum. The gum was fractionated by chromatography (silica; diethyl ether) to give the required product, 2.38 g, as a yellow oil.
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[CH2:2]2.[Cl:16][C:17]1[N:18]=[C:19](Cl)[C:20]2[N:25]=[CH:24][S:23][C:21]=2[N:22]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:12][C:19]3[C:20]4[N:25]=[CH:24][S:23][C:21]=4[N:22]=[C:17]([Cl:16])[N:18]=3)[CH:13]=[CH:14][CH:15]=1)[CH2:2]2
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: Nc1cccc(N2C[C@H]3CC[C@@H](C2)O3)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Clc1nc(Nc2cccc(N3C[C@H]4CC[C@@H](C3)O4)c2)c2ncsc2n1
Temperature: 30 °C
Yield: 84.7 %

Procedure:
The mixture of 3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline (0.061 g, 0.3 mmol), 5,7-dichlorothiazolo[5,4-d]pyrimidine (0.061 g, 0.3 mmol) and DIPEA (0.046 g, 0.36 mmol) in DMSO (10 mL) was heated to 30° C. for 2 h. Then it was diluted with water and extracted with ethyl acetate (3×10 mL), the organics were dried and concentrated. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with MeOH:DCM=1:80) to afford N-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (0.095 g, 86%) as a yellow solid. LC-MS: 374 [M+H]+, tR=1.66 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH3:22])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>N1C=CC=CC=1>[C:24]([O:21][C:18]([CH3:20])([CH3:19])[C:17]#[C:16][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:23])[N:9]([CH3:22])[CH2:10][C:11]=12)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN1Cc2c(C#CC(C)(C)OC(=O)C(C)(C)C)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 24 h
Yield: 23.2 %

Procedure:
3.30 g (10 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy -3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzo diazepin-6-one were dissolved in 20 ml of pyridine and treated at room temperature with 1.57 g (13 mmol) of pivaloyl chloride. The reaction mixture was stirred at 65° for 24 hours and then evaporated. The residue was taken up in methylene chloride, the solution was washed once with lN hydrochloric acid and twice with water, dried over magnesium sulfate and evaporated. By chromatography on silica gel while eluting with ethyl acetate and subsequent crystallization from ethyl acetate and hexane, there was obtained 0.96 g (23%) of 3-(7-chloro-5,6-dihydro-5-methyl -6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-1,1-dimethyl-2-propynyl pivalate of melting point 132-133°.