Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:25][CH:24]3[CH2:26][CH:21]2[CH2:22][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11]([NH:41][C:38]3[CH:37]=[CH:36][C:35]([N:32]4[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]4)=[CH:40][CH:39]=3)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:25][CH:24]3[CH2:26][CH:21]2[CH2:22][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C2CC3CCC2C3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(C2CC3CCC2C3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester (1.5 g, 7.1 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.6 g, 7.1 mmol) were combined in CH2Cl2 (20 mL) and triethylamine (1.0 g, 10 mmol) was added. After 16 h, water (10 mL) was added the organic layer was separated, dried (MgSO4), and concentrated. Chromatography (10-50% EtOAc/hexanes gradient) provided 1.8 g of 4-[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.8 g, 4.4 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4), and concentrated. Recrystallization from i-PrOH provided 0.51 g of 8-bicyclo[2.2.1]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 8-Bicyclo[2.2.1]hept-2-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.12 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.59 (s, 1H), 7.52 (d, 2H, J=8.9 Hz), 6.87 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.52-3.62 (m, 4H), 3.28 (br s, 2H), 2.98 (br s, 2H), 2.82 (s, 3H), 2.14-2.53 (m, 5H), 1.58-1.75 (m, 4H), 1.22-1.42 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:13]=[C:12]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:11]=1>CN(C)C=O.O>[Br:1][C:2]1[NH:3][CH2:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:11]=2)[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrC1=CN(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)CN1
Temperature: 120 °C

Procedure:
To a cooled solution of 4-bromo-1H-imidazole (0.249 g, 2.0 mmol) in anhydrous dimethylformamide (4 ml) was slowly added sodium hydride (60% dispersion in mineral oil) (0.088 g, 2.2 mmol). When the evolution of gas has ceased (30 mins), 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (3b)(0.571 g, 2.00 mmol) was added in a single portion and the resulting mixture heated in a microwave reactor at 120° C. for exactly 14 minutes (fixed temperature holdtime, high absorbtion setting). The resulting brown/yellow slurry was diluted with water (10 ml) and filtered. The filter cake was washed with cold water (2×10 ml) and then dried in a vacuum dessicator to give the title compound in suitably pure form to be used without further purification. m/z (LC-MS, ESP): 396 [M+H]+, R/T=3.61 mins.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[CH:20]=[CH:21][C:22]([NH:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4])=[O:23]
Reactant: COc1ccc2ccc([C@@H](N)CO)cc2c1
Reactant: O=C(O)C=Cc1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ccc([C@H](CO)NC(=O)C=Cc3c(F)cccc3F)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
A mixture of (R)-2-Amino-2-(7-methoxy-naphthalen-2-yl)-ethanol (0.1 mmol), 2,6-difluorocinnamic acid (0.1 mmol), EDC·HCl (0.2 mmol), DMAP 0.1 mmol), triethyl amine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography eluting with 5% methnol in ethyl acetate to provide the title compound as a solid (25 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>CC(C)=O>[C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:30]3[C:26](=[O:36])[C:27]4[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:29]3=[O:31])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c1
Reaction time: 17.5 h

Procedure:
10 g (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D2) is dissolved in acetone and 6.5 g potassium phthalimide is added and the mixture is stirred for 17.5 h. The suspension is filtered and the product is purified by crystallization.
Reaction SMILES: C(O)C.Cl[C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1
Reactant: Nc1ccccn1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(Nc2ccccn2)nc1C(F)(F)F
Temperature: 80 °C
Yield: 24.6 %

Procedure:
A reaction vessel was charged with 100 ml ethanol, 13.0 g (50 mmol) ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate and 9.41 g (100 mmol) 2-aminopyridine. The reaction mixture was heated at a temperature of about 80° C. for 80 hours. The mixture was cooled to room temperature. This mixture was diluted with water and extracted three times with ethyl ether. The combined ether extracts were washed with large amounts of water, dried over magnesium sulfate, and concentrated under reduced pressure to give 19.1 g of a brown, wet, solid material. This material was recrystallized from a 1:1 ethanol:water solution over a 36-hour period. The recrystallized material was suction filtered to give 3.9 g of a dark brown solid material which was triturated in warm hexane to give 2.3 g of brown solid product (m.p. 07°-111° C.) identified in Table I.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:11]([S:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:13])[CH3:12].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH:11]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]ccc3n2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
2-bromo-5H-pyrrolo[2,3-b]pyrazine (6.5 g, 32.82 mmol), (4-isopropylsulfonylphenyl) boronic acid (7.859 g, 34.46 mmol) and palladium triphenylphosphane complex (1.896 g, 1.641 mmol) were combined in a round bottomed flask. To this mixture was added dioxane (97.50 mL) and then an aqueous solution of Na2CO3 (49.23 mL of 2 M, 98.46 mmol). The resulting suspension was stirred at 100° C. overnight, then heating was stopped and water added. The resultant precipitate was collected and dried in vacuo at 40° C., to give the sub-title compound as a brown solid (9.45 g, 95% yield). 1H NMR (400.0 MHz, DMSO) δ 12.25 (s, 1H), 9.00 (s, 1H), 8.43 (d, J=8.4 Hz, 2H), 7.99-7.96 (m, 3H), 6.74 (d, J=3.5 Hz, 1H), 3.57 (s, 1H) and 1.20 (d, J=6.8 Hz, 6H) ppm; MS (ES+) 435.2.
Reaction SMILES: Cl.[CH:2]([N:5]([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:6](=[O:8])[CH3:7])([CH3:4])[CH3:3].F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([N:12]2[CH2:11][CH2:10][CH:9]([N:5]([CH:2]([CH3:4])[CH3:3])[C:6](=[O:8])[CH3:7])[CH2:14][CH2:13]2)=[CH:17][CH:18]=1)=[O:21]
Reactant: CC(=O)N(C(C)C)C1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C(C)C)C1CCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 71.3 %

Procedure:
To a solution of N-isopropyl-N-(piperidin-4-yl)acetamide hydrogen chloride (0.260 g, 1.41 mmol) in DMF (5 mL) was added 4-fluorobenzaldehyde (0.18 mL, 1.69 mmol) and K2CO3 (0.233 g, 1.69 mmol). The resulting solution was heated to 120° C. overnight, and cooled. The cooled solution was diluted with water and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% MeOH/CH2Cl2, to afford N-(1-(4-formylphenyl)piperidin-4-yl)-N-isopropylacetamide (0.290 g, 71%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]1[CH:13]2[N:8]([CH2:9][CH2:10][CH:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=4)[NH:16][CH:15]=3)[CH2:12]2)[CH2:7][CH2:6]1>CN(C)C=O>[CH3:1][NH:2][C:3]([NH:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH:13]2[N:8]([CH2:7][CH2:6][CH2:5]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reaction time: 72 h
Yield: 55.8 %

Procedure:
The methylisocyanate (220 mg, 3.9 mmol) was added to a solution of 3-(octahydroindolizin-7-yl)-5-amino-1H-indole (500 mg, 1.95 mmol) in 10 ml of dimethylformamide. The reaction was allowed to stir for 72 hours. TLC indicated the reaction was complete so the reaction was concentrated to give a purple gum. This material was chromatographed on a short FLORISIL™ column using 20% methanol in methylene chloride (ammonium hydroxide) as solvent to give 340 mg of a white foam. The white foam was recrystallized from methanol/ethyl acetate to give 165 mg of product. (27.1%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[C:11]([CH:12]=[O:13])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:5])[CH3:4].O>C1COCC1>[C:3]([C:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.2 %

Procedure:
Sodium borohydride (50 mg, 1.3 mmol) was added to a solution of 2-[2-(3-tert-Butyl-4-formylpyrazol-1-yl)-acetylamino]-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (100 mg, 0.25 mmol) in THF (2 mL). The mixture was stirred for 1 h at ambient temperature. Water was added and the product extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using eluants EtOAc/heptane. The solid isolated was further purified by preparative reverse phase HPLC and passed down an SCX cartridge. The volatiles were blown off with nitrogen to give a white solid (2.4 mg, 0.61 μmol, 2%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[OH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:41][CH2:42][NH:43]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:41][CH2:42][NH2:43]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)c(F)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Temperature: 150 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 28, 3.0 g, 10 mmol), 1,1′-azobis(N,N (3.5 g, 21 mmol), triphenylphosphine (5.4 g, 21 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (3.3 g, 21 mmol) and DCM (20 mL) were added. The mixture was heated at 150° C. for 20 minutes in a microwave heater. The reaction mixture was allowed to cool to room temperature and TFA (20 mL) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude material was filtered through a plug of silica gel using DCM as eluent. The solvent was removed under reduced pressure and the crude material was dissolved in ethyl acetate (10 mL) and the HCl salt of the title compound precipitated when 1 M HCl in diethylether (20 mL) was added. The solid was filtered off, dissolved in DCM (100 mL) and organic phase was washed with saturated aqueous NaHCO3 (40 mL) to give the title compound (2.0 g). MS m/z 335 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH:29]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].O1CCCC1>C(OCC)C>[O:34]([CH:29]([O:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)[C:30]([O:32][CH3:33])=[O:31])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)C(Br)Oc1ccccc1
Reactant: Cc1cc(C)nc(O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccccc1)Oc1nc(C)cc(C)n1
Reaction time: 48 h

Procedure:
Alternately, the tetrabutylammonium salt of 4,6-dimethyl-2-pyrimidinol was first prepared by placing 4,6-dimethyl-2-hydroxypyrimidine (13.0 g, 0.105 mol) in a flask, adding 65 g of 40 percent aqueous tetrabutylammonium hydroxide (0.10 mol), and removing the water by evaporation under reduced pressure at pressures down to about 10 mm Hg (1.33 kPa) at 40°-45° C. The residue amounted to 42.7 g and appeared to be a dihydrate of the desired salt. A 10.9 g portion of this (25 mmol) was placed in a 500 mL flask containing 25 mL of tetrahydrofuran. A cloudy solution formed. To this was added with stirring at ambient temperature 14 mL of a solution of methyl 2-bromo-2-phenoxyacetate in tetrahydrofuran (containing about 25 mmol). The resulting mixture was allowed to stir for 2 days. Analysis by gas-liquid chromatography indicated only one significant compound was present. A 250 mL portion of diethyl ether was added and the resulting mixture was extracted 5 times with 100 mL portions of water and then with brine. The ethereal solution was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound in crude form as a dark borwn oil. This was filtration chromatographed on silica gel eluting first with a 10:90 mixture of diethyl ether and hexane and then with a 15:85 mixture of ethyl acetate and hexane. The product containing eluate was concentrated by evaporation under reduced pressure to obtain 2.50 g (35 percent of theory) of the title compound as a pale yellow oil. This oil solidified on standing to a light orange solid melting at 50°-53° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCCOCCO
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCCOCCO

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 2-(2-aminoethoxy)ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[NH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)=[CH:12][C:3]1=2.C1C(=O)N([Br:28])C(=O)C1.O>C1COCC1>[Br:28][C:17]1[CH:16]=[C:15]([C:18]#[N:19])[NH:14][C:13]=1[C:11]1[CH:10]=[CH:9][C:4]2[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:20])([CH3:1])[C:3]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To 4,4-dimethyl-6-(5-cyano-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (0.625 g, 2.3 mmol, 1 eq) in THF (anhydrous, 60 mL) was added NBS (0.46 g, 2.5 mmol, 1.1 eq) at −78° C. After 1 hour, the reaction was warmed to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with aqueous 10% sodium bisulfite solution (50 mL), water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexane gave the product (40 mg, 5%) as a white solid. The filtrate (0.5 g) was placed aside. 1H NMR (300 MHz, d6-DMSO): δ 1.64 (s, 6H), 6.98 (d, 1H, J=8.2 Hz), 7.19 (d, 1H, J=1.4 Hz), 7.57 (s, 1H), 7.62 (dd, 1H, J=1.4, 8.3 Hz), 10.43 (s, 1H), 12.91 (s, 1H). MS (ESI) [M−H]−m/z 344/346. Anal. calcd. for C15H12BrN3O2: C, 52.04; H, 3.49; N, 12.14. Found: C, 51.4; H, 3.57; N, 11.59.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[C:9]([Mg]Cl)#[CH:10]>C1COCC1>[OH:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]#[CH:10]
Reactant: C#C[Mg]Cl
Reactant: O=Cc1ccccn1
Solvent: C1CCOC1
Product: C#CC(O)c1ccccn1

Procedure:
3-Hydroxy-3-(2-pyridinyl)-1-propyne was prepared according to Method A above from 2-pyridine carboxaldehyde (1.0 g, 9.3 mmol) (Aldrich) in THF (50 mL) and ethynylmagnesium chloride (10 mmol, 20 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 956 mg, 77%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[S:8][CH2:7]1
Reactant: ICCCCCI
Reactant: O=C1CSCN1CCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1N(CCCCBr)CSC12CCCCC2
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (25 g) in tetrahydrofuran (350 ml) cooled to -60° C., was added 1,5-diiodopentane (100 g). The resulting slurry was allowed to cool to -65° C. and a solution of lithium bis(trimethylsilyl)amide in hexanes (220 ml) was added dropwise over a period of 30 minutes while maintaining the internal temperature at or below -55° C. The resulting mixture was stirred for 15 minutes and the internal temperature allowed to rise to 0° C. 0.5N HCl (500 ml) was added to quench the reaction and the mixture was concentrated in vacuo to remove the THF. The aqueous mixture was extracted twice with 250 ml portions of ether, washed with water (400 ml) and brine (400 ml), dried (Na2SO4) and concentrated to a liquid. The liquid was chromatographed on silica gel (elution with 20% ethyl acetate/hexane) to give a liquid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@H:19]([CH:20]=[C:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[C@H:18]1[C:29]([OH:31])=[O:30].[C:33]([C@@H:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)#[N:34]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][C:17]1([CH3:16])[C@H:19]([CH:20]=[C:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[C@H:18]1[C:29]([O:31][C@H:35]([C:33]#[N:34])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:37]=1)=[O:30]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C(C)=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)=C=C[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
A mixture of 1.3 g of dicyclohexylcarbodiimide and 30 mg of 4-dimethylamino-pyridine in 15 ml of dichloromethane were added to a solution of 1.5 g of the product of Step E, 1.42 g of (S)α-cyano-3-phenoxy-benzyl alcohol and 30 ml of dichloromethane and the mixture was stirred at 20° C. for 18 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 4-1 hexane-ethyl acetate mixture yielded 1.16 g of (S)α-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3-(3-ethoxycarbonyl-1,2-butadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+35° (chloroform).
Reaction SMILES: [H-].[Li+].[CH3:3][C:4]1([CH3:13])[C@@H:6]([CH:7]([OH:9])[OH:8])[C@H:5]1[C:10]([OH:12])=O.[CH3:14][O:15][CH2:16]CCl.[Na]>O1CCCC1>[CH3:13][C:4]1([CH3:3])[C@@H:5]([CH:10]=[O:12])[C@H:6]1[C:7]([O:8][CH2:14][O:15][CH3:16])=[O:9]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(O)O
Reactant: COCCCl
Agent: [H-]
Agent: [Li+]
Agent: [Na]
Solvent: C1CCOC1
Product: COCOC(=O)[C@@H]1[C@H](C=O)C1(C)C
Reaction time: 0.5 h

Procedure:
70 ml of acetyl chloride were added with stirring to a mixture of 90 ml of methylal and 2.4 ml of methanol and the mixture was allowed to stand for several hours to obtain chloromethyl methyl ether. 6.7 g of lithium hydride were added over 30 minutes at about 15°±2° C. to a solution of 110 g of the lactone of (1R,cis) 2,2-dimethyl-3-dihydroxymethyl-cyclopropane-carboxylic acid in 500 ml of tetrahydrofuran and after stirring the mixture for 30 minutes, the mixture containing chloroethyl methyl ether was added thereto. The mixture was stirred at 20° C. for four hours and was poured into aqueous sodium bircarbonate solution. The mixture was extracted with isopropyl ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 117 g of raw product which was distilled to obtain methoxymethyl (1R,cis) 2,2-dimethyl-3-formyl-cyclopropane-carboxylate with a boiling point of 65° to 70° C. at 5×10 -2 mm Hg.