Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:24][CH2:23]4)[O:19][N:18]=3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:26].C(OCC)C>C(Cl)Cl>[ClH:26].[CH:22]1([C:20]2[O:19][N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:8]4([NH2:7])[CH2:9][CH2:10]4)=[N:12][CH:13]=3)[N:21]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3noc(C4CC4)n3)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NC1(c2ccc(-c3noc(C4CC4)n3)cn2)CC1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To the solution of {1-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (80 mg, 0.23 mmol) in CH2Cl2 (10 mL) was added 4M HCl (2 mL, 8 mmol). After stirring overnight, more 4M HCl (0.1 mL, 0.4 mmol) was added. After a total of 42 h, diethyl ether (10 mL) was added to the reaction mixture and stirring was continued for 10 min. The reaction suspension was filtered and the solid was washed with ether (10 mL) to afford 1-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridin-2-yl]-cyclopropylamine HCl salt (40 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][O:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of 195.9 g of 2-hydroxy-3-methyl-4'-chlorobenzophenone [Huston et al., JACS, Vol. 73, (1951), p. 2483] in 1 liter of dimethylformamide was added with stirring to a suspension of 40.8 g of sodium hydride in 200 ml of dimethylformamide and the mixture was stirred for 1 hour with cooling in an ice-water bath. Then, a solution of 170.4 g of methyl iodide in 800 ml of dimethylformamide was added thereto over 40 minutes and the mixture was then stirred for 16 hours in the ice-water bath. The mixture was filtered to remove insolubles and the filtrate was treated with activated carbon, filtered and was evaporated to dryness under reduced pressure. The residue was taken up in 1 liter of ether and 200 ml of water and the aqueous phase was reextracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and was eluted with methylene chloride to obtain 171 g of 2-methoxy-3-methyl-4'-chlorobenzophenone in the form of colorless crystals melting at 43° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]2[CH2:10][N:9]([O:11][CH2:12][C:13]3C=C[CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:20]1C=CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH:1]1([CH2:6][C@@H:7]2[CH2:10][N:9]([O:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:20]3)[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1[C@H](CC2CCCC2)CN1OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: O=C1[C@H](CC2CCCC2)CN1OC1CCCCO1
Yield: 100 %

Procedure:
(3R)-3-(Cyclopentylmethyl)-1-[(phenylmethyl)oxy]-2-azetidinone (100 g, 386 mmol) was dissolved in ethanol (1.2 L), and the solution was degassed. Pd on C (10%, dry, 8 g) was added and the suspension was purged with hydrogen and stirred under a hydrogen atmosphere (balloon) until the reaction was complete by LC-MS (approximately 6 h). The suspension was then sparged with nitrogen, filtered through Celite, and evaporated to dryness. The resulting solid was redissolved in CH2Cl2 (1 L) and dihydropyran (70 mL, 767 mmol) was added, followed by pyridinium p-toluenesulfonate (PPTS, 5%, 4.85 g). The reaction mixture was stirred 3 days at room temperature, then concentrated and chromatographed on silica gel using 10-20% ethyl acetate in hexanes to provide (3R)-3-(cyclopentylmethyl)-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone as a colorless liquid (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:29])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=[O:17])[CH:11]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:10][CH:9]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:29])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[C:25]([OH:27])=[O:26])[CH:11]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:10][CH:9]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)(=[O:38])=[O:39]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CNC(=O)C1CC(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 45.9 %

Procedure:
A The process is performed as described in Example 1A, but starting with 2 g of (2RS,4SR,5RS)-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-methoxycarbonylphenyl)ureido]acetyl}-4-(4-nitrophenyl)sulphonylpyrrolidine and 0.16 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.9 g of (2RS,4SR,5RS)-3-(3-{2-[5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(4-nitrophenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.2; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 383 K, δ in ppm): 0.94 (d, J=6.5 Hz, 6H: C(CH3)2); 1.89 (mt, 1H: CH); from 2.65 to 3.00 (2 mts, 1H each: CH2 at 3); 3.08 (mt, 2H: NCH2); 3.72 and 3.91 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.21 (mt, 1H: H4); 4.83 (t, J=7.5 Hz, 1H: H2); 5.71 (d, J=3 Hz, 1H: H5); from 6.95 to 7.65 (mt, 6H:aromatic H); 8.02 (mt, 1H: aromatic H (H2: ortho to the COOH)); 8.18 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 8.25 (d, J=8.5 Hz, 2H: H of the aromatic at 4 (H meta to the NO2)); 8.42 (d, J=8.5 Hz, 2H: H of the aromatic at 4 (H ortho to the NO2))].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCOCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[S:26]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:27])=[O:28]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Reaction time: 8 h

Procedure:
Aniline hydrochloride (64.8 mg, 0.05 mmol) is dissolved in 1,4-dioxane (1 ml) in a reaction tube and Na2CO3(85 mg) dissolved in water (0.5 ml) is added. To this mixture is added 2-Chloro-5-(2-oxo-propyl)-benzenesulfonyl chloride (115 mg, 0.43 mmol) (Intermediate A, prepared as described in WO03072557, page 77) in 1,4-dioxane (1 ml). The reaction mixture is left at room temperature overnight and monitored by LC-MS. The reaction mixture is shaken overnight with amino polystyrene (300 mg) and macroporous-isocyanate (300 mg), filtered and the resin is washed with MeOH (0.5 ml). The filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(NCc2ccccc2Cl)cc1
Temperature: 45 °C

Procedure:
A solution of 2-chlorobenzaldehyde (70 g.) and 4-methoxyaniline (61.5g.) in toluene (750 ml.) was refluxed under a Dean and Stark separator until no more water collected (ca. 1 hour). The toluene was evaporated in vacuo, and the residue was dissolved in methanol (1.5 l.). The methanolic solution was treated at room temperature with sodium borohydride (60 g.) added portionwise so that, with gentle cooling, the temperature was maintained at 40-50° C. The solution was then refluxed for 15 minutes, diluted with water (1.5 l.), and the aqueous mixture extracted with ether (3 × 200ml.). The combined ethereal extracts were washed with water (2 × 100 ml.), dried (K2CO3), and evaporated to give N-(4-methoxyphenyl)-2-chlorobenzylamine as a brown oil, Infra Red ν max 3400, 1618 cm.-1, which was used directly in the next stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)([OH:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To an ice-cooled solution 3,3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 7.2 mmol) in THF (20 ml) was added 4-chlorophenylmagnesium bromide (1 M in ether, 15 ml, 15 mmol). The solution was allowed to warm to about room temperature, then stirred at room temperature for about 22 hours. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[N:16]1([CH:21]2[CH:30]3[CH:25]([CH2:26][CH2:27][CH2:28][NH:29]3)[CH2:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>CCOCC>[ClH:8].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([N:29]1[CH:30]2[CH:25]([CH2:24][CH2:23][CH2:22][CH:21]2[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:26][CH2:27][CH2:28]1)=[O:7]
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C(=O)N2CCCC3CCCC(N4CCCC4)C32)cc(OC)c1OC
Yield: 36.3 %

Procedure:
510 mg of 3,4,5-trimethoxybenzoyl chloride and 417 mg of the product of Step C of Example 1 were reacted in ether for 40 hours at ambient temperature and the crude product obtained in the form of the base was converted into the hydrochloride as in Example 1 to obtain 319 mg of the expected product melting at ≈260° C.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:42])[CH:14]([CH3:41])[CH:15]2[CH2:27][CH2:28][C:29](=[O:40])[CH2:30][CH:31]([OH:39])[CH2:32][C:33]([O:35]CC=C)=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:42])[CH:14]([CH3:41])[CH:15]2[CH2:27][CH2:28][C:29](=[O:40])[CH2:30][CH:31]([OH:39])[CH2:32][C:33]([OH:35])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)CC(O)CC(=O)CCC1C(C)C(=O)C=C2C(=NOCc3ccccc3)CCC(OC(=O)C(C)CC)C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCC(C)C(=O)OC1CCC(=NOCc2ccccc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)O)C21
Reaction time: 18 h
Yield: 48.9 %

Procedure:
239 mg (0.4 mmole) of allyl 7-[5-benzyloxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoate (prepared as described in Example 1a) were dissolved in 3.3 ml of anhydrous tetrahydrofuran, and 20.7 mg (0.02 mmole) of tetrakis(triphenylphosphine)palladium (0), 21.5 mg (0.08 mmole) of triphenylphosphine and 31 μl (0.82 mmole) of formic acid were added to the solution, and the resulting mixture was stirred for 18 hours under an atmosphere of nitrogen. At the end of this time, the reaction mixture was condensed by evaporation under reduced pressure, and the residue was dissolved in a 50% v/v aqueous solution of acetonitrile. The solution was filtered through a SEP-PAK C-18 Cartridge (Trade name for a product of Waters Co.) and extracted with ethyl acetate. The resulting ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and condensed by evaporation under reduced pressure. The resulting oily residue was purified through a reverse phase Lobar Column (RP-18, Size B, Merck), using as the eluent a buffer solution consisting of a 1:1 by volume mixture of acetonitrile and aqueous phosphoric acid (pH 3.0) containing 0.001M of triethylamine, to obtain 106 mg (yield 48%) of the title compound as an oily substance.
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:10][C@@:2]12[CH2:1][C@@H:6]([O:13][C:11]1=[O:12])[C@H:5]1[C@H:4]([O:9][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:8]1)[CH2:3]2
Reactant: O=Cc1ccccc1
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1O[C@@H]2C[C@@]1(O)C[C@H]1OC(c3ccccc3)O[C@@H]21
Temperature: -20 °C
Yield: 39.6 %

Procedure:
The procedure in J. Org. Chem. 1995, 50, 888-890 was followed. Briefly, a solution of quinic acid (20.0 g, 0.104 mol), benzaldehyde (16.6 g, 156 mmol) and para-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol) in toluene (350 mL) was refluxed for 10 hours in a flask equipped with a Dean-Stark trap. The reaction mixture was cooled, washed with saturated NaHCO3 solution and brine, dried (MgSO4). Filtered and concentrated. The concentrate was dissolved in 1:1 hexanes/ethyl acetate (100 mL) and cooled to −20° C. for 2 hours to provide 10.8 g (40%) of the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.S(=O)(=O)(O)O.[CH:16]1C=CC=CC=1>CO>[O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1ccc[nH]c1=O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc[nH]c1=O

Procedure:
A mixture containing 27.8 g of 1,2-dihydro-2-oxo-3-pyridinecarboxylic acid, 3.0 ml of concentrated sulfuric acid in 500 ml of methanol, and 300 ml of benzene are heated under reflux for 2.5 hours. A Dean-Stark trap is then attached, and the azeotrope collected is removed periodically in 25 ml fractions over a period of 28 hours. The remaining solvent is removed by evaporation under reduced pressure and the solid residue suspended in 500 ml of cold water. The suspension is filtered (from which unreacted starting material can be recovered) and the filtrate continuously extracted with methylene chloride. The extracts are concentrated under reduced pressure to yield the title compound as a white solid which, upon recrystallization from,,l 4 L..of benzene, yields 19.48 g (64%) of methyl 2-oxo-1,2-dihydro 3-pyridinecarboxylate: m.p. 148°-151° C.; NMR (DMSO-d6, 80 MHz) delta 3.72 (s, 3H), 6.25 (dd, 1H, J=7.1 Hz, J=6.3 Hz), 7.64 (dd, 1H, J=6.3 Hz, J=2.2 Hz), 8.03 (dd, 1H, J=7.1 Hz, J=2.2 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[N:20][CH:21]=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34]>CCO>[ClH:34].[ClH:34].[OH:27][NH:26][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]1[CH:18]=[N:17][C:16]([NH:15][C@@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10]2)=[CH:21][N:20]=1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCc3ccccc3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCc3ccccc3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To the solution of (2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (3.2 g, 7.1 mmol) in EtOH (16 ml) was added 2M ethanlic hydrogen chloride (17.5 mL) and the mixture was stirred at ambient temperature for 3 hrs. To the reaction mixture was added IPE and isolated precipitate was collected by filtration to give (2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride (2.3 g, 74%) as an amorphous powder.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:6]([F:19])[CH:5]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([N:27]2[C@@H:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][O:29][C:28]2=[O:35])[C:24]([F:36])=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[CH:18][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([N:27]4[C@@H:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][O:29][C:28]4=[O:35])[C:24]([F:36])=[CH:23][N:22]=3)[CH3:3])=[CH:5][C:6]=2[F:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Reactant: C[C@H](N)c1ccc(C(=O)NC2CCCCC2)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1nc(N[C@@H](C)c2ccc(C(=O)NC3CCCCC3)c(F)c2)ncc1F
Temperature: 125 °C
Yield: 8.4 %

Procedure:
To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061 mmol) was added (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (31.4 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125° C. for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 2.5 mg of N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 488.2 (M+H)+, Rt 0.99 min.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#[N:2].[BrH:11].[OH-].[Na+]>>[NH2:2][C:1]1[NH:6][C:5]([Br:11])=[C:4]([C:7]#[N:8])[C:3]=1[C:9]#[N:10]
Reactant: Br
Reactant: N#CC(C#N)=C(C#N)C#N
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)[nH]c(Br)c1C#N

Procedure:
Tetracyanoethylene (1) is reacted with HBr followed by treatment with a base such as NaOH produced 2-amino-5-bromo-3,4-dicyanopyrrole (3). Treatment of 3 with triethyl orthoformate followed by the addition of sodium hydride and 1 equivalent of the appropriate alkylating agent, with a catalytic amount of tetrabutylammonium iodide, gives the intermediate (5). The synthetic route is dependent upon correctly placing the alkyl substituents on the N7 position. Alkylation of 5 before cyclization controls the regiochemistry. Reaction of 5 with methanolic ammonia affords the 7-alkylated-4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidines (6). Thus, by selecting the appopriate alkyl substiuent, the desired 7-alkylated-4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidines can be prepared.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20]CC)=O)=[C:11]2[OH:23])(=O)C.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:18]([C:12]2[CH:13]=[N:14][C:15]3[C:10]([C:11]=2[OH:23])=[CH:9][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[CH:17][CH:16]=3)=[O:20])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cnc2ccc(NCCOC(C)=O)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(NCCO)cc2c1O
Temperature: 160 °C

Procedure:
To a flask containing ethyl 6-{[2-(acetyloxy)ethyl]amino)-4-hydroxy-3-quinolinecarboxylate (0.04 g) is added p-chlorobenzylamine (0.5 mL). The reaction is tightly capped and heated to 160° C. overnight. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 3% to 10% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.02 g of the title compound as a yellow solid.
Reaction SMILES: C([Si](C)(C)[C:6]1[N:10]([CH3:11])[C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[Cl:21])[CH:13]=2)=[CH:8][N:7]=1)(C)(C)C.Cl>CO.O>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[N:10]([CH3:11])[CH:6]=[N:7][CH:8]=3)[S:20][C:19]=12
Reactant: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: Cn1cncc1-c1cc2nccc(Cl)c2s1
Yield: 84.6 %

Procedure:
2-[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-7-chloro-thieno[3,2-b]pyridine (912 mg, 2.50 mmol) was dissolved in 15 mL of methanol and 10 mL of 1N aqueous hydrochloric acid and heated to 35° C. overnight. The solution was cooled, diluted with water, and extracted with ethyl acetate (3×30 mL). The aqueous layer was made basic (pH 9) with 1N aqueous sodium hydroxide and extracted with chloroform (3×30 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated to afford 528 mg (84%) of 7-chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine. 1H NMR (400 MHz, CD3OD) δ8.58 (d, 1H), 7.84 (s, 1H), 7.68 (s, 1H), 7.47 (d, 1H), 7.42 (s, 1H), 3.93 (s, 3H). LC-MS: 250.1, 252 (MH+); HPLC RT: 4.40 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 95.8 %

Procedure:
To a solution of ethyl [4-({(2-methoxyethyl)[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (500 mg, 0.97 mmol) in THF (6 mL) and MeOH (6 mL) was added NaOH (2M; 3 mL) and the resultant solution stirred for 2 h at room temperature. The mixture was concentrated in vacuo, acidified with 2M HCl and extracted with CH2Cl2. The organic solution was dried (Na2SO4) and the solvent removed in vacuo to afford the title compound as a colourless oil (453 mg).
Reaction SMILES: [SH:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CC#N.ClCCl>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:12][S:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[CH3:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Sc1nc2ccccc2[se]1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C(=O)CSc1nc2ccccc2[se]1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a suspension of 2-mercaptobenzselenazole (418 mg, 2 mmol) in 4 mL of MeCN and 4 mL of dichloromethane with vigorous stirring was added dropwise, ethyl bromopyruvate (290 mg, 2 mmol). The resulting mixture was stirred for 5 h. It was allowed to settle for 30 min and then filtered. The solid was washed with EtOAc/hexanes (1:1, 2×8 mL) and dried in high vacuum to afford 3-(benzoselenazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester as a white powder (582 mg, 89%). 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.14-8.10 (m, 1H), 7.95-7.92 (m, 0.7H), 7.75-7.73 (m, 0.3H), 7.52-7.45 (m, 1H), 7.36-7.30 (m, 1H), 7.07 (s, 0.7H), 4.69 (s, 0.6), 4.37-4.27 (m, 2H), 1.32 (t, J=7 Hz, 3H). MS(ESI) m/z: 330(M+H+, 55), 348 M++H2O, 58 ), 362 (M++MeOH, 100).