Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.C(OC)(=O)/C=C/CCC(OC)=O.[C:17]([CH:22]1[CH:26]([CH:27]=[CH2:28])[CH2:25][CH2:24][C:23]1=[O:29])([O:19][CH2:20]C)=[O:18].C(OC)(=O)C=C>C1COCC1.[Cu]Cl>[CH2:27]([CH:26]1[CH2:25][CH2:24][C:23](=[O:29])[CH:22]1[C:17]([O:19][CH3:20])=[O:18])[CH3:28]
Reactant: C=CC1CCC(=O)C1C(=O)OCC
Agent: Cl[Cu]
Agent: CC[Mg]Br
Agent: COC(=O)/C=C/CCC(=O)OC
Solvent: C=CC(=O)OC
Solvent: C1CCOC1
Product: CCC1CCC(=O)C1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A round bottom flask was charged with copper(I) chloride (0.0575 g, 0.581 mmol) and purged with N2. A solution of 1M ethylmagnesium bromide in THF (23.2 mL, 23.2 mmol) was injected and the mixture was cooled to 0° C. A solution of (E)-dimethyl hex-2-enedioate (2 g, 11.6 mmol) in anhydrous THF (10 mL) was injected over 15 minutes, and the reaction was stirred for 30 minutes at 0° C. (E)-Dimethyl hex-2-enedioate was prepared as described in Nugent, William A. and Frank W. Hobbs, Jr. “Conjugate Addition-Cyclization of a Cyanocuprate: 2-Carboethoxy-3-vinylcyclopentanone.” Organic Syntheses. Vol. 66 (1988): pp. 52-59, using methyl acrylate (100.00 mL, 1110.5 mmol), anhydrous LiBF4 (9.109 g, 97.17 mmol), and tetrakis(acetonitrile)palladium (II) tetrafluoroborate (1.332 g, 2.998 mmol). The reaction was warmed to room temperature and stirred at room temperature for 1 hour. TLC (5:1 EtOAc/Hexanes) showed disappearance of the UV-active starting material spot. The reaction was concentrated to a solid under vacuum and partitioned between DCM and saturated aqueous NH4Cl. The organic was washed with brine and dried over anhydrous Na2SO4. The reaction produced methyl 2-ethyl-5-oxocyclopentanecarboxylate (1.88 g, 11.0 mmol, 95.1% yield) as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.76 (s, 3H), 2.84 (d, 1H), 2.2-2.6 (m, 4H), 1.62 (m, 1H), 1.41-1.52 (m, 2H), 0.96 (t, 3H). MS (APCI+) [M+H]: 171.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.C1(O)C=CC=CC=1.[Na].[K].[OH-]>O>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1
Reactant: COCCc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [K]
Agent: [Na]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O
Product: COCCc1ccc(OCC2CO2)cc1

Procedure:
p-(2-Methoxyethyl)phenol (A) and epichlorohydrin (B, 1.4-2.0 eqv.) are reacted in water, at least 1.5 kg, preferably about 2 kg of water per kg of phenol, during the addition of sodium (or potassium) hydroxide solution, (1.3-1.7 eqv.) to form 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)benzene; (p-methoxyethyl-epoxypropoxybenzene). The reaction is preferably performed at a temperature of 50-70° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][S:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][S:52][CH2:51][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: C1CSCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCSCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[C-]#N.[Na+].[Cu](C#N)[C:21]#[N:22].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O.O.O.S([O-])([O-])(=O)=O.[Ni+2]>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[C:21]#[N:22]
Reactant: N#C[Cu]C#N
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Agent: [Ni+2]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 95 °C
Reaction time: 2 h
Yield: 391.4 %

Procedure:
A suspension of 10 g of 2-chloro-4-trifluoromethylaniline in 18 g of 95% sulphuric acid and 65 ml of water is slowly added at 15° C. to a solution of 3.57 g of sodium nitrite in 7 ml of water. The reaction mixture is stirred at 40°-45° C. for 2 hours and then carefully poured onto the following mixture maintained at 95° C.: 10.77 g of sodium cyanide, 0.51 g of copper cyanide, 25.8 g of sodium hydrogencarbonate and 0.46 g of nickel sulphate hydrate in 30 ml of water. The reaction mixture is stirred at 100° C. for 1 hour and then, after cooling, 30 ml of a saturated aqueous sodium hydrogencarbonate solution are added and extraction is carried out with dichloromethane. The extract is filtered through celite and then successively washed with water, with salted water, dried over sodium sulphate and evaporated to dryness. The residue is purified on a column of silica gel, eluent: 20/1 (v/v) cyclohexane/ethyl acetate, and 3.55 g of 2-chloro-4-trifluoromethylbenzonitrile are obtained in the form of a brown oil. 1H NMR (CDCl3): 7.4 to 7.8 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28]O)[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(S(F)(F)[F:36])CC)C>ClCCl>[F:36][CH2:28][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1
Reactant: Nc1nc2ccccc2c2c1nc(CO)n2Cc1cc(-c2ccc(F)cc2)no1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CF)n2Cc1cc(-c2ccc(F)cc2)no1
Temperature: -78 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
The methods described in Examples 30 and 31 were repeated on a larger scale to provide (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol. The reaction described in Example 31 was heated at reflux and was complete within three hours. Under a nitrogen atmosphere, a suspension of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol (2.31 g, 5.93 mmol) in dichloromethane (100 mL) was cooled to −78° C. (Diethylamino)sulfur trifluoride (DAST) (0.95 mL, 7.2 mmol) was added dropwise. The mixture was stirred for 30 minutes at −78° C. and then was allowed to warm to room temperature slowly and stirred for one hour. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous potassium carbonate. Additional dichloromethane and water were added to dissolve solids. The aqueous layer was separated and extracted with dichloromethane. The combined organic fractions were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 3% to 5% CMA in chloroform) followed by recrystallization from acetonitrile. The crystals were dried under high vacuum for 18 hours at 90° C. to provide 0.994 g of 2-(fluoromethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 192.0-193.0° C.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N:16]#[C:17][NH2:18].C([O-])(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[NH2:18][C:17]1[O:1][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:16]=1
Reactant: N#CN
Reactant: CCCCCCCCCCCC(=O)CO
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1coc(N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.5 %

Procedure:
To a solution of 1-hydroxy-2-tridecanone (1.0 g, 4.7 mmol) and cyanamide (0.2 g, 5 mmol) in THF (3.0 mL) was added aqueous sodium acetate (2.0 mL, 1.0 N), tetra n-butylammoniumhydroxide (0.6 mL, 0.4 N 0.2 mmol), and sodium hydroxide (0.2 mL, 1.0 N, 0.2 mmol) sequentially. The resulting two-phase mixture was stirred (48 hours, 25° C.). The resulting mixture was taken up in ethyl acetate (200 mL), washed with brine (2×65 mL), dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica (pure chloroform to 95:5 chloroform:methanol) and concentrated in vacuo to yield 0.70 g (63%) of the title compound as an off-white powder, m.p. 55°-58° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](Cl)=[O:15]>C(=S)=S>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][CH:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]2=[O:15]
Reactant: CC(C)CC(Cc1ccccc1Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)CC1Cc2c(Br)cccc2C1=O
Reaction time: 1 h
Yield: 105.6 %

Procedure:
A 500-ml four-necked round flask equipped with a stirrer, a Dimroth condenser, a dropping funnel, a thermometer and a NaOH trap was charged with 20.33 g (152.5 mmol) of anhydrous aluminum chloride and 70 ml of carbon disulfide. To the mixture was added dropwise a solution containing 40.2 g (132.6 mmol) of the above-obtained 3-(2-bromophenyl)-2-i-butylpropionic acid chloride dissolved in 50 ml of carbon disulfide under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature in the flask was elevated to room temperature, and the mixture was stirred for 1 hour. Then, the reaction mixture was quenched by pouring onto 200 ml of ice water, which was then extracted with 100 ml of ether three times. The combined organic phase was washed with 100 ml of a saturated aqueous solution of sodium bicarbonate, and then 100 ml of a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give 37.4 g of the desired product as an orange liquid. This ketone was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH3:26])=[O:20]
Reactant: CC(C)(C)CN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)CNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2,2-dimethylpropylamine (0.310 g, 3.56 mmol), triethylamine (0.280 g, 2.77 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2,2-dimethylpropyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.660 g, 53.1% yield).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([Cl:12])([Cl:11])[Cl:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:14]([S:16]Cl)=[O:15]>ClC1C=CC=CC=1>[O:15]=[C:14]1[NH:1][C:2]([C:9]([Cl:10])([Cl:11])[Cl:12])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:16]1
Reactant: O=C(Cl)SCl
Reactant: CCOC(=O)/C=C(\N)C(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: CCOC(=O)c1sc(=O)[nH]c1C(Cl)(Cl)Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
to 130.14 g (1.00 mole) of ethyl acetoacetate was added 1.5 g of sodium. The reaction temperature increased spontaneously to 50° C. The reaction mixture was cooled with an ice bath. To the cooled reaction mixture was added, with vigorous stirring at 30°-50° C., 144.3 g (1.00 mole) of trichloroacetonitrile in 30 minutes. After complete addition of the trichloroacetonitrile, the reaction mixture was cooled with a dry ice bath. No precipitate of the ethyl 2-acetyl-3-amino-4,4,4-trichlorocrotonate formed. Part of the above product was stirred with 100 ml. of concentrated 28-30% ammonium hydroxide for 2 hours. The reaction mixture was then extracted with ether. The ether solution was dried (CaSO4) and concentrated to give 180 g (82.5%) of crude ethyl 3-amino-4,4,4-trichlorocrotonate. Part of this crude material (20 g) was distilled at 0.5 mm Hg to give 11.7 g of pure product, m.p. 91°-95° C. To a cold (10° C.) solution of 21.8 g (0.0937 mole) of crude ethyl 3-amino-4,4,4-trichlorocrotonate in 15 ml. of chlorobenzene was added 13.5 g (0.103 mole) of chlorocarbonylsulfenyl chloride. The reaction temperature rose spontaneously to 35° C. after the ice water bath was removed. The reaction mixture was stirred at 65° C. for 1 hour, cooled and triturated with petroleum ether to give 10.3 g (38%) of ethyl 2,3-dihydro-2-oxo-4 -trichloromethyl-5-thiazolecarboxylate, m.p. 109°-110° C. A mixture of 14.5 g (0.05 mole) of ethyl 2,3-dihydro-2-oxo-4-trichloromethyl-5-thiazolecarboxylate, 10.4 g ) 0.05 mole) of phosphorus pentachloride, and 100 ml. of phosphorus oxychloride was held at reflux for 7 days. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with ice water and the aqueous mixture was extracted with ether. The ether solution was extracted with 10% sodium hyroxide, dried (CaSO4) and concentrated under reduced pressure to give 3.2 g of oil which was chromatographed on silica gel using 5% ethyl acetate-petroleum ether as eluant. The first 1.2 l. of eluant gave 2.27 g of solid which was recrystallized from petroleum ether at low temperature to give 2.13 g (13.8%) of ethyl 2-chloro-4-trichloromethyl-5-thiazolecarboxylate, m.p. 42.5°-43.5° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[O:34][C:35](=[O:37])[CH3:36])=[O:27]>ClCCl>[C:35]([O:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])(=[O:37])[CH3:36]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a separate reaction flask, to a stirred solution of gabapentin (1.8 g, 10 mmol) and triethylamine (4.3 mL, 31 mmol) in dichloromethane (100 mL) at 0° C. under nitrogen atmosphere, was added dropwise a solution of chlorotrimethylsilane (2.6 mL, 21 mmol) in dichloromethane (10 mL). After stirring for 30 min at 0° C., 2(R)-acetoxycyclopent-1(R)-yl chloroformate was added dropwise into the reaction mixture. The resulting mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h (monitored by TLC). The reaction mixture was then concentrated in vacuo and the resulting residue was poured into cold water (50 mL), acidified to about pH 5.0 using 0.1 N HCl, then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluant to afford 2.0 g (84%) of compound 48 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ1.31-1.78 (14H, m); 2.03-2.04 (5H, m); 2.31 (2H, s); 3.20 (2H, t, J=6.4 Hz); 5.07-4.97 (2H, m), 5.20 (1H, broad s). MS (ESI): m/z=340.25 (M−H−).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O.CCO>[CH2:1]([O:8][CH2:9][C:10]1[NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[N:21][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccnc1NC(=O)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(COCc2ccccc2)nc2ncccc12
Yield: 18.7 %

Procedure:
2-(2-Benzyloxy-acetylamino)-nicotinamide (76 mg, 0.3 mmol) in H2O/EtOH (4 ml, 1:1) was stirred with sodium carbonate (28 mg, 0.3 mmol) at reflux for 2 hours. Water was added, the phases were separated and the inorganic layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo to yield 2-benzyloxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one (15 mg, 21%) as a white solid, MS (m/e): 268.1 [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:13]2[NH:14][C:15](=[O:23])[NH:16][C:17](=[O:22])[C:18]=2[CH:19]([CH3:21])[CH3:20])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1N=C(Cl)[C:28]([CH:32](C)[CH3:33])=[C:27](Cl)N=1.C([O-])([O-])=O.[K+].[K+].[I-].[Li+].CS(C/C=C/C)(=O)=O>CN(C=O)C.CCOCC>[CH2:27]([N:14]1[C:13]([N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:10](=[O:12])[CH3:11])=[C:18]([CH:19]([CH3:21])[CH3:20])[C:17](=[O:22])[NH:16][C:15]1=[O:23])[CH:28]=[CH:32][CH3:33]
Reactant: CC(=O)N(c1cc(C)cc(C)c1)c1[nH]c(=O)[nH]c(=O)c1C(C)C
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: C/C=C/CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC=CCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 13 h
Yield: 54 %

Procedure:
To a stirred solution of N-(3,5-dimethyl-phenyl)-N-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-acetamide (106) (prepared similarly to compound 109 in Scheme 36, below, except that 2,4,6-trichloro-5-isopropyl-pyrimidine was used instead of 2,4,6-trichloro-5-ethyl-pyrimidine) (600 mg, 1.9 mmol) anhydrous powdered K2CO3 (262 mg, 1.9 mmol), and lithium iodide (254 mg, 1.9 mmol) in DMF (7 mL), was added 1-methanesulfonyl-trans-2-butene (269 μL, 2.28 mmol). After stirring for 13 hr., the reaction mixture was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 382 mg (54%) of a white solid. m.p. 103-105° C.; m/z (EI) 369(M+).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:26][C:27]1[O:31][C:30]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:28]=1>C(#N)C>[C:17]([C:9]1[C:10]([C:13]([F:15])([F:16])[F:14])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:26][C:27]1[O:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1)[C:4]([CH2:1][CH2:2][CH3:3])=[CH:12]2)#[N:18]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.7 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.500 g, 1.98 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (6.50 g, 20.0 mmol) along with ethyl 5-(chloromethyl)-2-furancarboxylate (0.561 g, 3.00 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was mixed with 1.0N LiOH (25 mL) and anhydrous 1,4-dioxane (2 5 mL) and the mixture was stirred at rt for 17 h. The mixture was diluted with water and extracted with Et2O. The organics were separated and the aqueous mixture was made acidic using 1.0N HCl. The aqueous mixture was extracted with EtOAc, dried (MgSO4) and concentrated to dryness to give a crude solid (0.579 g, 78%). This solid was used without further purification.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([OH:18])C2C(=CC=CC=2)C=CC=1.C>[I-].C([N+](CC)(CC)CC)C.[Rh]>[CH:1]1([N:7]=[C:8]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc2ccccc12
Reactant: NC1CCCCC1
Agent: [Rh]
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Product: O=C=NC1CCCCC1

Procedure:
The carbonylation reaction is conducted in the same manner as in Example 1 except that 25 mmol of cyclohexylamine, 86 g of α-naphthol, 1.5 g of Rh/C having 5% Rh carried on activated charcoal and 1 mmol of tetraethylammonium iodide are employed. As a result, the yields of cyclohexyl isocyanate and α-naphthyl cyclohexyl carbamate are 58% and 10%, respectively.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6](=[O:37])[CH:7]([N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:18])=[C:12]2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]3[O:27][C:28]4[C:34](C)=[CH:33][C:32](C)=[CH:31][C:29]=4[N:30]=3)=[CH:21][CH:20]=2)=[N:10]1)[CH3:8].O1C2C=CC=CC=2N=C1NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[CH3:38][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:37])[CH:7]([N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:18])=[C:12]2[C:11]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]3[O:27][C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)=[CH:23][CH:24]=2)=[N:10]1)[CH3:8]
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C(C)C(=O)NCCN(C)C)c5ncnc(N)c45)cc3)nc2c1
Agent: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)cc2)OC1(C)C
Product: CC(C(=O)NCCN(C)C)n1nc(-c2ccc(Nc3nc4ccccc4o3)cc2)c2c(N)ncnc21

Procedure:
The procedure described in the preparation of N1-[2-(dimethylamino)ethyl]-2-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanamide was employed, except that the Suzuki coupling procedure employed N-(1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 5.5-7.0 min) afforded N1-[2-(dimethylamino)ethyl]-2-{4-amino-3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}propanamide as an off-white solid (0.003 g, 0.006 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 6.70 min;
Reaction SMILES: C(N1C(C)=C(I)N=C1CCC)C.[CH3:13][C:14]1[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[N:16][C:15]=1[C:23]#[C:24][Si](C)(C)C>>[C:23]([C:15]1[N:16]=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:14]=1[CH3:13])#[CH:24]
Reactant: Cc1c(C#C[Si](C)(C)C)nc2n1CCCC2
Agent: CCCc1nc(I)c(C)n1CC
Product: C#Cc1nc2n(c1C)CCCC2
Yield: 50.5 %

Procedure:
As described for example 3a, 1-ethyl-4-iodo-5-methyl-2-propyl-1H-imidazole (2.60 g, 9.92 mmol) instead of 2-amino-5-bromopyridine was converted to 3-methyl-2-trimethylsilanyl-ethynyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine (SiO2, dichloromethane:methanol=100:0 to 98:2, 890 mg, 39%) which was obtained as a dark brown semisolid and used further without detailed characterization. As described for example 3b, 3-methyl-2-trimethylsilanylethynyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine (890 g, 3.83 mmol) instead of 5-trimethylsilanyl-ethynyl-pyridin-2-ylamine was converted to the title compound (SiO2, ethyl acetate, 310 mg, 51%) which was obtained as a light brown solid. MS: m/e=161.3 [M+H]+.