Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:16][CH2:15]1)(=[O:12])=[O:11])=[O:4].[OH-].[Li+]>O1CCCC1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:17]2([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:18][CH2:19][CH:14]([CH2:13][S:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:5]3[C:3]([OH:4])=[O:2])(=[O:11])=[O:12])[CH2:15][CH2:16]2)(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)[C@H]1CCCN1S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CCCN1S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of (R)-1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-pyrrolidine-2-carboxylic acid methyl ester (Example 18) (108 mg, 0.19 mmol.) in tetrahydrofuran (10 mL) was added lithium hydroxide (18 mg) in water (4 mL) and the mixture vigorously stirred for 1.5 hours. After removal of the solvent in vacuo, the aqueous residue was acidified to pH 1 with 2N aqueous hydrochloric acid and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:acetic acid (30:60:1), to afford the desired MS (ES+) 562 ([MH]+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:15][CH3:16])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 6-bromopicolinic acid (14.25 g, 70.3 mmol) in anhydrous ethanol (250 ml) was slowly added thionyl chloride (60 ml) at 5° C. After the addition was completed, the ice-bath was removed and the mixture was stirred at 25° C. for 3 hr. The solvent was evaporated under vacuum, the aqueous residue basified with saturated sodium carbonate, and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to give ethyl 6-bromopicolinate as a white solid (15.75 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[O:17]([CH2:24][CH2:25][N:26]1[CH2:30]C[C@@H:28](O)[CH2:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[O:17]([CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: O[C@@H]1CCN(CCOc2ccccc2)C1
Solvent: Cc1ccccc1
Product: O=C(O[C@@H]1CCN(CCOc2ccccc2)C1)C(O)(c1cccs1)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
1.33 g of 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester (0.0052 mol) were dissolved in 40 ml of toluene. To this solution were added 1.08 g (0.0052 mol) of (3R)-1-(2-phenoxyethyl)pyrrolidin-3-ol (Intermediate I-15), and 0.104 g (0.0026 mol) of HNa (60% dispersion in mineral oil). The mixture was stirred 30 min at room temperature, refluxed for 45 minutes, and then refluxed with continuous removal of distillate with replacement with fresh toluene when necessary for 1.5 hours. The cooled mixture was extracted with 2N HCl acid, the aqueous layer basified with K2CO3 and extracted with CHCl3. The organic layer was washed with water, dried over Na2SO4 and evaporated to yield 1.77 g of an oil which was purified by chromatography on silica gel eluting with chloroform/ethanol/NH4OH (200:8:1). Appropriate fractions were combined and evaporated to yield 1.22 g of the title product as an oil (54.7%). This product was solidified by formation of the oxalate salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:12]Br>O1CCOCC1>[Br:12][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1)=[O:11]
Reactant: CC(=O)c1ccc(O)c(F)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(O)c(F)c1
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred solution of 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (2.0 g, 12.98 mmol) in dioxane (3 ml) was added a solution of bromine (2.09 g, 13.1 mmol) in dioxane (12 ml), and the mixture was stirred for 16 hours. The mixture was concentrated in vacuo to give title compound (3.02 g, 99% yield). The compound was used for next reaction without purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=O)[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:15])=O>>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:15])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nc(C)cc(Cl)n1

Procedure:
The pyrimidinone from Example 3 2-n-butyl-6-methylpyrimidin-4(3H)-one is converted to the title compound upon treatment with phosphoryl chloride as described by Gabriel amd Colman (Ber. 1899, 32, 2921) and by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1>>[NH2:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH3:22]
Reactant: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)CCc1c[nH]c2ccc(CN)cc12
Temperature: 25 °C

Procedure:
Lithium aluminium hydride (40.0 mg, 1.055 mmol, 1.5 equivalents) was placed in an argon purged oven dried flask fitted with a stirbar and condenser. Anhydrous diethylether (5 mL) was added and stirring begun. 3-(2-Dimethylamino-ethyl)-1H-indole-5-carbonitrile (57) (150.0 mg, 0.703 mmol, 1.0 equivalent) was dissolved in a separate dry flask in a mixture of anhydrous diethylether (5 mL) and anhydrous tetrahydrofuran (5 mL) and this solution added dropwise to the solution of lithium aluminium hydride and the resulting mixture heated to reflux. After 30 minutes the reaction was cooled to room temperature and quenched with distilled water (50 μL), aqueous 3N sodium hydroxide solution (75 μL) and distilled water (150 μL) sequentially. The solution was filtered and concentrated. The residue was purified via silica gel column chromatography (10-15-20% 2M NH3 in methanol/90-85-80% dichloromethane) to provide 2-(5-(aminomethyl)-1H-indol-3-yl)-N,N-dimethylethanamine (58) as a pale yellow residue (73 mg, 47.8% yield). 1H NMR (DMSO) δ: 2.21 (s, 6H), 2.53 (m, 2H), 2.78 (t, 2H), 3.79 (s, 2H), 7.02-7.05 (d, 1H), 7.09 (s, 1H), 7.24 (d, 1H), 7.44 (s, 1H), 10.66 (br s, 1H). MS: 218 (M+1), 201 (M+1—NH3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]([OH:32])([CH:30]=[CH2:31])[CH3:29])[CH3:24])[CH3:19])[CH3:14].C1(C)C=CC=CC=1>C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:31][CH2:30][C@:28]([CH2:27][CH2:26][CH2:25][C@@H:23]([CH2:22][CH2:21][CH2:20][C@@H:18]([CH2:17][CH2:16][CH2:15][CH:13]([CH3:12])[CH3:14])[CH3:19])[CH3:24])([CH3:29])[O:32][C:6]=2[C:5]=1[CH3:9]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 99.2 %

Procedure:
Suspended in 20 ml of ethyl acetate were 10.0 g (65.8 mmol) of trimethylhydroquinone (TMH) and 0.32 g (0.658 mmol) of scandium trifluoromethanesulfonate, followed by heating under reflux for 10 minutes under an argon gas stream. After a solution of 20.3 g (68.4 mmol) of isophytol in 20 ml of ethyl acetate was added dropwise over 30 minutes under heating and reflux, TMH and isophytol were reacted for 3 hours. The reaction mixture was cooled, to which 100 ml of toluene were added. The resulting mixture was washed twice with 200-ml portions of water and then concentrated under reduced pressure. The residue was added with 100 ml of toluene and 100 ml of 2-butanone. The organic layer was washed twice with 200-ml portions of a 1N aqueous solution of sodium hydroxide and then with 200 ml of a saturated aqueous solution of sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: n-hexane-diethyl ether system), whereby 28.1 g of the title compound were obtained in the form of a brown oil. (Yield: 99%, GLC purity: 95%)
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:17](O)=[O:18])[CH2:2][CH2:3][CH3:4].B>O1CCCC1>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:17][OH:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C(=O)O)ccc2ccc(OC)cc12
Agent: B
Solvent: C1CCOC1
Product: CCCCc1c(CO)ccc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
As in Example 135, 1-butyl-7-methoxy-2-naphthalenecarboxylic acid (2.73 g) in tetrahydrofuran (15 ml) was treated with a solution of borane in tetrahydrofuran (1M; 22 mL) at 0°-5° C. and then mixture was stirred at room temperature overnight. The product was isolated in the usual manner and was crystallized from hexane to give 2.32 g of 1-butyl-7-methoxy-2-naphthalenemethanol, mp 52°-53° C. Anal. Calcd for C16H20O2 : C, 78.65; H, 8.25 Found: C, 78.50; H, 8.12
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:10]([CH2:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1
Reactant: ClCc1cnccn1
Reactant: CN1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Nc2nc3ccccc3n2Cc2cnccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a stirred mixture of 11.5 parts of N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine and 144 parts of N,N-dimethylformamide was added 5 parts of a sodium hydride dispersion 50%. AFter stirring for 1 hour at room temperature, a solution of 12.8 parts of 2-(chloromethyl)pyrazine in N,N-dimethylformamide was added dropwise to the thus obtained mixture. Upon complete addition, stirring was continued for 2 hours at 50° C. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.5 parts (9.3%) of N-(1-methyl-4-piperidinyl)-1-(2-pyrazinylmethyl)-1H-benzimidazol-2-amine; mp. 169.3° C. (compound 69).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.C(O)(C)C.O1CCCC1.C(N(CC)CC)C.ClCCl.CO>[Pd].CO>[CH2:7]1[CH2:8][NH:9][CH2:10][C:11]2[CH:2]=[N:3][C:4]3[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=3[C:6]1=2
Reactant: Clc1nc2ccccc2c2c1CNCC2
Agent: [Pd]
Solvent: CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: c1ccc2c3c(cnc2c1)CNCC3
Yield: 85.2 %

Procedure:
A 2 L heavy-walled glass Parr vessel equipped with a magnetic stirrer and stir bar was charged under nitrogen with 5-chloro-1,2,3,4-tetrahydrobenzo[c]-2,7-naphthyridine (30.0 g, 137 mmol), 2:1 (v/v) isopropanol-tetrahydrofuran (1100 mL), triethylamine (40.0 g, 395 mmol) and 10% by weight palladium on carbon (3.0 g). The vessel was vacuum-degassed three times, releasing the vacuum with nitrogen each time, and evacuated three times, pressurizing with hydrogen each time. The hydrogen pressure was adjusted to 55 psi and the batch was stirred at ambient temperature for 16 hours. The catalyst was filtered-off through Celite (40 g) and the filter cake was rinsed with methanol (350 mL). The filtrate and rinse were concentrated to give a light yellow solid. The solid was swished with 5:1 (v/v) dichloromethane-methanol (50 mL), collected on a filter and dried to constant weight in a vacuum oven at 40° C. This first crop material was blended with additional product obtained from the filtrate after it was in turn purified by chromatography. The filtrate was concentrated in vacuo to provide a solid, which was dissolved in a little methanol and loaded onto a 10 g KP-Sil samplet. The samplet was allowed to dry before inserting it into a 100 g KP-Sil SNAP cartridge that had been pre-equilibrated with 3 CV of 10% (v/v) 5 N ammoniacal methanol-dichloromethane. The cartridge was attached to a Biotage unit and eluted with a gradient of 5 N ammoniacal methanol-dichloromethane as follows: 10% v/v (2 CV), 10-14% v/v (5 CV), 14-16% v/v (4 CV), and 16-18% v/v (4 CV). Pure fractions were pooled and concentrated under reduced pressure to obtain the product, which was thoroughly blended with the first crop material to afford the title compound as a yellow solid (21.5 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:16][CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[CH:16][CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1nccc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)n1
Product: CC(C)C(=O)Nc1nccc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)pyrimidine-4-carboxamide (17 mg, 0.05 mmol, Step-1) and isobutyryl chloride (17 mg, 0.16 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[Mg].II.[C:16]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: O=C1CCCC1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(C3OCCO3)cc2)CCCC1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-bromophenyl)-[1,3]dioxolane (1.15 g, 5.00 mmol) in THF (5.0 ml) is added dropwise at 55° C. to magnesium turnings (146 mg, 6.0 mmol) and a crystal of iodine in THF (5 ml). The mixture is stirred for 1 h at 55° C. Then a solution of cyclopentanone (465 μl, 5.25 mmol) in THF (5 ml) is added dropwise and the mixture is stirred for another hour at 55° C. The reaction mixture is diluted with THF, acidified with 1 N HCl (4 ml) and washed three times with brine. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(4-[1,3]dioxolan-2-yl-phenyl)-cyclopentanol as yellow oil; HPLC/MS 1.71 min (A), [M+H] 235.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([O:18][CH3:19])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].ClC(Cl)(Cl)C([N:24]=C=O)=O.C[O-].[Na+]>>[CH2:1]([C:5]1[N:6]([O:18][CH3:19])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCCc1nc2cnc3ccccc3c2n1OC
Agent: C[O-]
Agent: [Na+]
Product: CCCCc1nc2c(N)nc3ccccc3c2n1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
The methods described in Parts C and D of Example 20 were used to oxidize and aminate 2-butyl-1-methoxy-1H-imidazo[4,5-c]quinoline (3.2 g, 12.5 mmol) with the following modifications. The oxidation reaction was stirred for two hours at room temperature. The reaction with trichloroacetyl isocyanate (2.2 mL, 19 mmol) was carried out at room temperature overnight, and the reaction sodium methoxide was stirred overnight and then concentrated under reduced pressure. The residue was treated with methanol (5 mL) to form a solid, which was collected by filtration and recrystallized from methanol/water and dried overnight in a vacuum oven at 70° C. to provide 0.946 g of 2-butyl-1-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as golden crystals, mp 197-199° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:7][CH:8]=1)[CH3:2].I[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([C:3]1[C:4](=[O:18])[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:7]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CI
Reactant: CCc1c[nH]c(CCc2ccc(F)cc2)nc1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn(CC(=O)OC(C)(C)C)c(CCc2ccc(F)cc2)nc1=O
Yield: 78.8 %

Procedure:
5-Ethyl-2-[2-(4-fluorophenyl)ethyl]-1H-pyrimidin-4-one (B40) (955 mgs) in dichloromethane (20was treated with t-butyl iodoacetate, (2.82 g) and diisopropylethylamine (2.03 mls) at room temperature for 3 days. The solution was washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulphate. The solution was concentrated to give a semi-solid which was triturated with ether:dichloromethane, 5:1, giving the title compound as a white solid, (1.101 g, 79%), 1H-NMR (CDCl3) δ 1.16 (3H, t), 1.47 (9H, s), 2.47 (2H, q), 2.74 (2H, t), 3.14 (2H, t), 4.27 (2H, s), 6.90 (1H, s), 6.98 (2H, m) and 7.17 (2H, m). (APCI+) Found (M+1)=361, C20H25FN3 requires 360.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.[C:11]([C:15]1[CH:16]=[C:17]([OH:25])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:21]([C:19]1[CH:18]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:20]=1)[O:25][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[CH:6]=[CH:7][CH:8]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(OCc2cccc(C#N)c2)cc(C(C)(C)C)c1

Procedure:
Using the method of Example 1, 20.6 g (0.10 mole) of alpha-bromo-m-tolunitrile was reacted with 3,5-di-t-butylphenol to give white crystalline 3-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile. Analysis: Calculated for C22H27NO: %C 82.2; %H, 8.4; %N, 4.4; Found: %C, 82.2; H, 8.5; %N, 4.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][NH2:14])[CH3:9].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH2:8]([O:10][C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][NH:14][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:9]
Reactant: CCOC(=O)C(C)CN
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)CNc1ccccc1
Yield: 41 %

Procedure:
To a solution of 4.904 g (0.020 mole) of (rac)-3-amino-2-methyl-propanoic acid ethyl ester trifluoroacetate in 30 mL of dimethylsulfoxide was added 4.08 g (0.020 mole) of iodobenzene, 0.46 g (0.004 mole) of L-proline, 0.38 g (0.002 mole) of copper (I) iodide and 19.57 g (0.060 mole) of cesium carbonate. Argon was bubbled through the solution for 15 minutes. The mixture was then heated at 80 degrees for 16 hours. After cooling, the mixture was partitioned between ethyl acetate (2×300 mL) and water (3×300 mL). The organic layers were washed with 300 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography, eluting with dichloromethane-hexanes (80:20) and then dichloromethane gave 1.70 g of (rac)-2-methyl-3-phenylamino-propionic acid ethyl ester as colorless oil that darkened on standing.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([O:25]C)=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1.O.[OH-].[Li+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.7 %

Procedure:
A mixture of methyl (±)-8-[3-(pyrimidin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.071 g, 0:18 mmol) and lithium hydroxide monohydrate (0.009 g, 2 mmol) in THF (5 mL) and H2O (2 mL) was stirred at room temperature for 18 hr, then was concentrated. The residue was dissolved in H2O and the pH was adjusted to 4 with 3 N HCl. The resulting solid was collected by filtration and dried to give the title compound (0.05 g, 73%) as a white solid: MS m/e 371.4 (M+H)+. Anal. Calcd for C19H22N4O4.0.5 H2O: C, 60.15; H, 6.11; N, 14.77. Found: C, 60.14; H, 6.06; N, 14.71.
Reaction SMILES: [CH3:1][N:2]1[O:9][CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][N:2]1[O:9][CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CON(C)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1OCC2CNCC21

Procedure:
13 g (65 mmol) of ethyl 2-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux in 300 ml of water with 41 g of Ba(OH)2.8H2O overnight. Potassium carbonate is added, the barium carbonate which has precipitated out is filtered off with suction and the filtrate is extracted ten times with 100 ml of chloroform each time. The extract is dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=1)CCC.I[C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].[F-].[K+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:15]1([CH3:17])[CH2:14][O:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33][CH3:34])=[O:32])=[N:16]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1C1=NC(C)(C)CO1
Reactant: COC(=O)c1cccc(I)c1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2ccccc2C2=NC(C)(C)CO2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.4 %

Procedure:
A suspension of 1-tri(n-butyl)stannyl-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)benzene (5 g), methyl 3-iodobenzoate (2.17 g) and tetrakis(triphenylphosphine) palladium(0) (0.29 g) in dioxane was refluxed for 18 hours. After being cooled to room temperature, 25% potassium fluoride aqueous solution (11 ml) was added to the reaction mixture and the mixture was stirred for 15 minutes. Insoluble material was filtered by using celite The filtrate was extracted with ethyl acetate (50 ml), washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (200 g) with benzene-ethyl acetate (20:1) as an eluent. The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from methanol to afford methyl 3-[2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl]benzoate (370 mg).