Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([CH:12]([O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][CH:14]([CH3:16])[CH3:15])(O)=[O:10].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][NH:2][C:9]([CH:12]([O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH3:8]
Reactant: CC(C)CC(OC[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)C(CC(C)C)OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 14 h

Procedure:
Triethylamine, 1.15 g (0.0114 mol), is added to 1.59 g (0.0114 mol of ethyl glycinate hydrochloride in 200 ml of dichloromethane at 0°. To the previous suspension at 0° C. is added 4 g (0.0114 mol) of (2S)-phenylmethyl 2-[(1-carboxy-3-methylbutoxy)methyl]-1-pyrrolidinecarboxylate (center on side chain is R,S mixture), 1.74 g (0.0114 mol) of 1-hydroxybenzotriazole and 2.35 g (0.0114 mol) of dicyclohexylcarbodiimide. The mixture is allowed to reach room temperature and stirred 14 hours, filtered, the solvent evaporated in vacuo and the residue dissolved in 200 ml of dichloromethane and washed successively with a 5% aqueous solution of sodium carbonate, 2×200 ml, 10% aqueous solution of citric acid, 2×200 ml, and a saturated aqueous solution of sodium chloride, 2×200 ml. The dichloromethane layer is separated, dried over sodium sulfate, evaporated in vacuo, and the residue purified by chromatography using silica gel and eluting with dichloromethanemethanol (98:2) to give (2S)-phenylmethyl 2-[[1-[[(2-ethoxy-2-oxoethyl)amino]carbonyl]-3-methylbutoxy]methyl]-1-pyrrolidinecarboxylate (center on side chain is R,S mixture), 4 g; [α]D25 -72.7° (c 0.33, methanol).
Reaction SMILES: [C:1]([CH2:4][C:5]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)([OH:3])=[O:2].O.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O>C1(C)C=CC=CC=1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:22][C:21]([CH2:20][C:5]1([CH2:4][C:1]([O:3][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[O:2])[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:23]
Reactant: CCCC1CCC(C2CCC(CC(=O)O)(CC(=O)O)CC2)CC1
Reactant: OCCCCCCBr
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(CC(=O)OCCCCCCBr)(CC(=O)OCCCCCCBr)CC2)CC1

Procedure:
10.0 g (30.8 mmol) of (4-carboxymethyl-4′-propylbicyclohexyl-4-yl)acetic acid are heated on a water separator for 6 h together with 15.0 g (80.4 mmol) of 6-bromo-1-hexanol and 0.50 g (2.90 mmol) of paratoluenesulfonic acid monohydrate in 150 ml of toluene. After cooling, the reaction mixture is subjected to absorptive filtration (SiO2, toluene), and the filtrate is concentrated to dryness. The crude product obtained in this way is used directly for the next reaction.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH2:19]([CH2:21][NH2:22])[OH:20].Cl>O1CCOCC1.C1C=CC=CC=1>[OH:20][CH2:19][CH2:21][NH:22][C:10](=[O:12])[CH:9]=[CH:8][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(C=CC(=O)O)cc1
Reactant: NCCO
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(C=CC(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 9.5 g (0.05 mole) of 4-acetylcinnamic acid [obtained according to G. H. Cleland, J. Org. Chem., 34, 744 (1969)], of 30 g of thionyl chloride and 40 cc of benzene was brought to reflux for 20 minutes. The solution was concentrated dry under low pressure. The residual solid was dissolved in 100 cc of dioxane and the resulting solution was added, dropy by drop at a temperature of 20° C., to a solution of 9.3 g (0.15 mole) of ethanolamine in 50 cc of dioxane. The mixture was stirred for 1 hour at room temperature, poured into a mixture of 500 g of ice and 20 cc of 10N hydrochloric acid then extracted with chloroform. The organic phase was washed with water and dried on sodium sulfate. By evaporation of the solvent under low pressure there was obtained N-(2-hydroxyethyl)-4-acetylcinnamamide which was purified by recrystallization in ethylacetate. Melting point=124°-125° C. Yield: 4.2 g (36% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10]O.[OH-].[K+].CI>O>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CO
Reactant: Cc1ccc(O)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COc1ccc(C)c(C)c1
Yield: 81 %

Procedure:
To 3,4-dimethylphenol(19.3 g, 0.16 mol), methanol(150 ml) and KOH(9.65 g, 0.25 mol) were added and then refluxed for 2 hrs. Methyl iodide(36.5 g, 0.25 mol) was added thereto, refluxed for 3 hours and then followed by addition of water(150 ml). The resulting mixture was extracted with ethylacetate and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C.O1CCCC1>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])[C:20]=2[C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cc2)cc1
Yield: 98.7 %

Procedure:
A mixture of 4-tert-butyl-N-{5-(4-methylphenyl)-6-[2-(4-nitrophenoxy)ethoxy]pyrimidin-4-yl}benzenesulfonamide (383 mg), 10% palladium-carbon (50 mg) and ethanol-tetrahydrofuran (6 ml-3 ml) is subjected to catalytic hydrogenation at room temperature under hydrogen atmosphere (1 atm) for two hours. The catalyst is removed by filtration, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1), and recrystallized from ethyl acetate/diisopropyl ether to give N-{6-[2-(4-aminophenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (358 mg).
Reaction SMILES: [O:1]1[C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=[N:2]1.[CH:15]12[NH:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]2/[CH:22]=[CH:23]/[C:24]1[O:28][N:27]=[C:26](C(OCC)=O)[CH:25]=1.C12NC(CC1)CC2/C=C\C1ON=C(C(OCC)=O)C=1.Cl>>[O:1]1[C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=[N:2]1.[CH:15]12[NH:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]2/[CH:22]=[CH:23]/[C:24]1[O:28][N:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(/C=C/C2CC3CCC2N3)on1
Agent: CCOC(=O)c1cc(/C=C\C2CC3CCC2N3)on1
Agent: CCOP(=O)(Cc1ccno1)OCC
Agent: Cl
Product: C(=C/C1CC2CCC1N2)\c1ccno1

Procedure:
The manner in which arylethenyl- and arylethynyl-substituted 7-azabicyclo[2.2.1]heptane compounds of the present invention are synthetically produced can vary. Ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate can be utilized as a key intermediate in the synthetic pathway. Treatment of tropinone with ethyl chloroformate provides ethyl 8-aza-3-oxobicyclo[3.2.1]octane-8-carboxylate which is readily converted to ethyl 8-aza-2-bromo-3-oxobicyclo[3.2.1]octane-8-carboxylate upon treatment with bromine and 30% hydrogen bromide in acetic acid. Subsequent Favorski ring contraction using freshly prepared sodium ethoxide in ethanol provides ethyl 7-aza-2-(ethoxycarbonyl)bicyclo[2.2.1]heptane-7-carboxylate, as reported by Daly et al. Eur. J. Pharmacol. 321: 189-194 (1997). Di-isobutylaluminum hydride reduction of the ester functionality provides ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate in modest overall yield. Horner-Wadsworth-Emmons reaction between diethyl (5-isoxazolylmethyl)phosphonate and ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate provides a mixture of ethyl (E)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole carboxylate and ethyl (Z)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole carboxylate. The two isomers are readily separated by chromatography. Diethyl (5-isoxazolylmethyl)phosphonate is prepared according to the method described in Deshong et. al. J. Org. Chem. 53: 1356-1364 (1988). Deprotection of the amine functionality of ethyl (E)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole carboxylate using hydrochloric acid affords (E)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole. The synthesis of this compound is described as Example 1. Alternatively, the treatment of ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate with 5-(lithiomethyl)isoxazole and dehydration of the resulting alcohol as described in U.S. Pat. No. 6,022,868 to Olesen et. al. followed by removal of the ethyl carbamate protecting group will provide (E)- and (Z)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole.
Reaction SMILES: [CH2:1]([N:3]1[C:9]([CH3:11])([CH3:10])[C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH3:2].[Cl:12][C:13]([Cl:17])([Cl:16])[S:14]Cl.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH2:1]([N:3]1[C:9]([CH3:10])([CH3:11])[C:7](=[O:8])[N:6]([S:14][C:13]([Cl:17])([Cl:16])[Cl:12])[C:4]1=[O:5])[CH3:2]
Reactant: CCN1C(=O)NC(=O)C1(C)C
Reactant: ClSC(Cl)(Cl)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN1C(=O)N(SC(Cl)(Cl)Cl)C(=O)C1(C)C
Temperature: 7 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
A mixture of 15.6 g (0.1 mole) 1-ethyl-5,5-dimethylhydantoin (the product of Example 3), 19.5 g (0.1 moles) trichloromethylsulfenyl chloride and 1.2 g Aliquat® 336 in 100 ml methylene chloride was stirred vigorously for about 10 minutes. The reaction mixture was cooled to about 7° C. in an ice bath; 25 g (0.125 moles) of pre-cooled 20% aqueous sodium hydroxide were added at once. After the addition, the temperature of the reaction mixture rose to 27° C.; when the temperature returned to about 7° C., the ice bath was removed. The reaction mixture was washed three times with 50 ml ice water, dried over magnesium sulfate and stripped to give a solid. The solid was crystallized twice from toluene with charcoal treatment to give 16.0 g of the above-identified product as a white solid, melting point 141°-142° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([Cl:28])=[C:6]([C:8]2[C:9](=[O:27])[N:10]([CH2:25][CH3:26])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[Cl:28][C:5]1[C:6]([C:8]2[C:9](=[O:27])[N:10]([CH2:25][CH3:26])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:43]([NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])=[C:3]([F:29])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
To a solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-1,6-naphthyridin-2(1H)-one (500 mg, 1.20 mmol) and pyridine (140 mg, 1.8 mmol) in DCM (20 mL) was added phenyl isocyanate (215 mg, 1.8 mmol). The mixture was stirred at RT overnight, concentrated, and purified by prep-HPLC separation to give 1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (53 mg, 8.4% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.2 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.28-7.23 (m, 3H), 6.98-6.95 (m, 1H), 6.35 (s, 1H), 4.39 (s, 1H), 4.11-4.09 (m, 2H), 2.77-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.44-2.36 (m, 2H), 2.26 (s, 3H), 2.23-2.20 (m, 1H), 1.68-1.62 (m, 1H), 1.64 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.FC(F)(F)C(NC1C=CC(C#CCCCCO)=CC=1)=O.ClCCCC#C.[Br-:46].[Li+]>CCC(=O)CC>[Br:46][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(C#CCCCCl)cc1)C(F)(F)F
Reactant: [Br-]
Agent: C#CCCCCl
Agent: O=C(Nc1ccc(C#CCCCCO)cc1)C(F)(F)F
Agent: [Li+]
Solvent: CCC(=O)CC
Product: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F

Procedure:
A solution of N-(4-(5-chloropent-1-ynyl)phenyl)-2,2,2-trifluoroacetamide (10 mmol, prepared analogously to Intermediate 39, employing 5-chloropentyne in place of 5-hexyn-1-ol) in 3-pentanone (200 mL) was treated with lithium bromide (10 eq, 100 mmol). The mixture was heated to reflux for 16 hours, followed by concentration to dryness under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The concentrated organic phase was taken up again in 3-pentanone (200 mL) and heated to reflux for four hours in the presence of lithium bromide (10 eq, 100 mmol). The mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as an off-white solid. ES/MS calcd. for C13H12BrF3NO+ 334.0. Found m/z=334.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:14]/[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)/[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)/C(=C\C1CCOCC1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CO
Product: COC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C

Procedure:
A 250-mL pressure tube was charged with methyl (2E)-2-((tert-butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-2-propenoate (8.75 g, 30.7 mmol), MeOH (100 mL), and rhodium[(1R,1′R,2R,2′R)-2,2′-bis(1,1-dimethylethyl)-2,2′,3,3′-tetrahydro-1,1′-bi-1H-isophosphindole-κP2,κP2′][(1,2,5,6-η)-1,5-cyclooctadiene]tetrafluoroborate (0.209 g, 0.30 mmol, ChiralQuest, Monmouth Junction, N.J.). The mixture was stirred under a 50 psi (344 kilopascal) hydrogen atmosphere for 3 h. The mixture was then filtered through a pad of silica, washing with 1:1 EtOAc in hexanes, and then concentrated to give methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alaninate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH:15]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH2:9][CH2:10]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 43 %

Procedure:
The compound obtained from step 1 (0.4 g) was dissolved in ether, and cooled in an ice bath. LiAlH4 (0.1 g) was added slowly to the solution. The resulting mixture was reacted at room temperature for 1 hr. before adding water to end the reaction. The resulting solution was then extracted by using water and ester. An organic solution layer was dehydrated over magnesium sulfate, filtered, and concentrated under reduced pressure. The column chromatography was performed thereon, thereby obtaining crude yellowish liquid product (0.15, 43% yield) of the title.
Reaction SMILES: CCCP(=O)=O.[CH:7]1([C:10]2[C:11]([NH2:25])=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1.[N:26]1([C:30]([C:32]2[CH:36]=[N:35][N:34]([CH3:37])[C:33]=2[C:38](O)=[O:39])=[O:31])[CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH:7]1([C:10]2[C:11]([NH:25][C:38]([C:33]3[N:34]([CH3:37])[N:35]=[CH:36][C:32]=3[C:30]([N:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])=[O:39])=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
Propylphosphonic anhydride solution (50% in ethyl acetate, 0.59 ml) was added to a cooled (0° C.) solution of 6-cyclopropyl-2-phenyl-imidazo[1,2-a]pyridin-7-ylamine (100 mg, 0.40 mmol), 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (Step 3, 167 mg, 0.51 mmol), and N,N-diisopropylethylamine (311 mg) in ethyl acetate (3 ml). The mixture was stirred for 30 min at 0° C. and overnight at r.t. The reaction mixture was taken up in ethyl acetate, washed with water, dried (Na2SO4) and evaporated. The title compound (31 mg, 18%) was isolated from the residue by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=441.3 [M+H+].
Reaction SMILES: CB1N2CCCC2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[O:22]=[C:23]1[N:27]([C:28](=[O:40])[CH2:29][CH2:30][CH2:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[CH:26]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:25][O:24]1>>[OH:33][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:30][CH2:29][C:28]([N:27]1[CH:26]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:25][O:24][C:23]1=[O:22])=[O:40]
Reactant: O=C(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)C2CCCN12
Product: O=C(CCCC(O)c1ccccc1)N1C(=O)OCC1c1ccccc1

Procedure:
Under argon and at a temperature between 0° and −5° C., 5 g of 1-(2-oxo-4-phenyloxazolidin-3-yl)-5-phenylpentane-1,5-dione in 20 ml of dichloromethane are slowly, over a period of about 3 hours, added to a solution of 1.5 ml of boron-dimethylsulfide-complex in 25 ml of dichloromethane. The mixture is stirred at the same temperature for another 2 hours, the reaction being monitored by thin-layer chromatography. After the reaction has ended, 2 ml of methanol and 1.5 ml of 35 percent strength hydrogen peroxide solution and 1.1 ml of 3N sulfuric acid are added at below 0° C., and the mixture is stirred at room temperature for another 15 min. After phase separation, the organic phase is washed successively with 2N sulfuric acid, 5% strength sodium bisulfite solution and 10 percent strength sodium chloride solution and then dried and concentrated. After chromatography (SiO2, ethyl acetate/n-heptane=1:1, the product of molecular weight 339.4 (C20H21NO4); MS (DCl+): 322 (M+H+−H2O); (ESI+):403 (M+Na++CH3CN), 362 (M+Na+) is obtained. By adding optically active 1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (S or R, 0.75 ml) at from 0° to −5° C. to the reaction mixture prior to the addition of 1-(2-oxo-4-phenyloxazolidin-3-yl)-5-phenylpentane-1,5-dione, by the same route, 3 is obtained in diastereomerically enriched form.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([CH:12]=O)[C:3]=1[N:14]1[CH2:19][C@H:18]([CH3:20])[O:17][C@H:16]([CH3:21])[CH2:15]1.[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CC(O)C>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]2[C:3]=1[N:14]1[CH2:15][C@@H:16]([CH3:21])[O:17][C@@H:18]([CH3:20])[C@@H:19]1[C:28]1([C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]1=[O:30])[CH2:12]2
Reactant: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: Cc1noc2c(Cl)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 85 °C

Procedure:
To a solution of 7-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-methyl-1,2-benzoxazole-5-carbaldehyde (Intermediate 375, 35 mg, 0.119 mmol) in IPA was added barbituric acid (16 mg, 0.113 mmol) and the mixture heated at 85° C. for 16 hours. Solvents were evaporated and the residue thus obtained was purified over silica column using a gradient of methanol in chloroform to give product as a solid. Yield: 10 mg (25%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])[N:8]=1.Cl.[CH3:24][OH:25]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[NH:19])[O:25][CH3:24])[N:8]=1
Reactant: CO
Reactant: N#CCCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 60 h

Procedure:
The above nitrile (3 g.) was dissolved in dry chloroform (40 ml.) and MeOH (20 ml.), cooled to 0° and saturated with hydrogen chloride gas. The mixture was kept at 0° for 60 hours then volatile material was evaporated in vacuo. The residue was shaken with cold aqueous potassium carbonate solution (50 ml.) and extracted with chloroform (3×50 ml.). The combined extracts were dried (MgSO4) and evaporated in vacuo to give methyl 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valerimidate as a gum which was used without further purification.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([NH2:22])(=[O:21])[CH:19]=[CH2:20].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.CC(C)=O>[CH2:1]([NH:22][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(N)=O
Reactant: CCCCCCCCCCCCCCCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: C=CC(=O)NCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 250 ml capacity conical flask 13 g cetyl chloride (0.05 M), 3.5 g acrylamide (0.05 M) and 50 ml acetone were placed to obtain a clear solution. The solution was stirred with a magnetic needle at room temperature. 6.5 g anhydrous aluminium chloride (0.05 M) was added and the reaction mixture was stirred at room temperature. After 5 to 10 minutes of stirring, vigorous evolution of hydrogen chloride took place which ceased after about 5 minutes. Temperature of the reaction mixture was raised to 40 to 50° C. It was then cooled to room temperature and poured into 500 ml cold water. White product was precipitated. The product was isolated and purified by reprecipitation from acetone into cold water.