Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:18][CH2:19][O-:20].[Na+].[Na].C(O)C>CC(C)=O.O1CCOCC1>[CH2:19]([O:20][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:5]=[C:6]([Cl:11])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:18]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1c(Cl)nc(N2CCSCC2)nc1Cl
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1nc(N2CCSCC2)nc(Cl)c1[N+](=O)[O-]
Temperature: -20 °C

Procedure:
14.8 gm (0.05 mol) of 4,6-dichloro-5-nitro-2-thiomorpholino-pyrimidine were dissolved in a mixture of 200 ml each of acetone and dioxane, and the solution was cooled to -20°C. A solution of sodium ethylate, prepared from 1.15 gm (0.05 mol) of sodium and 100 ml of ethanol, was added dropwise while stirring, at -20°C. The mixture was stirred another hour at room temperature, then poured over ice, and the product obtained thereby was recrystallized from isopropanol. Yield: 10.3 gm (67.5% of theory); m.p. 149°-150°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[OH:15][NH2:16].C(=O)(O)[O-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[N:16][OH:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC(=NO)CC2
Yield: 78.4 %

Procedure:
A mixture of 7-methoxy-2-tetralone (0.50 g, 2.8 mmol), hydroxyl amine hydrochloride (0.38 g, 5.6 mmol) and sodium bicarbonate (0.47 g, 5.6 mmol) in methanol (20 mL) was heated to reflux for 3 h. The mixture was poured into water (15 mL) and extracted with chloroform. The organic phases were combined, washed with brine, and concentrated to give a white solid. Precipitation from ethyl acetate/hexane gave the title compound (420 mg, 79%) as a granular solid. MS(ES) m/e 191 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][C:11](Cl)=[CH:10][CH:9]1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC1=CC(Cl)=CC(C2CCCC2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Product: CC1=CCCC(C2CCCC2)N1C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-6-methyl-2-cyclopentyl-1,2-dihydropyridine (2.54 g, 8.53 mmol) in 175 mL of MeOH at 0° C. was added of lithium carbonate (0.63 g, 8.53 mmol) followed by 5% Pd/C. The mixture was placed under a positive pressure of hydrogen gas from a balloon, and the reaction progress was monitored by removing aliquots with a syringe, concentrating the aliquot in vacuo, and examining its 1H NMR spectrum. Upon completion, the mixture was filtered through Celite and evaporated. The residue was dissolved in ether (100 mL) and water (50 mL) was added, and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with 1M NaOH and brine. The organic phase was dried with potassium carbonate, filtered through Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 1.14 g (52%) as a clear oil that was homogeneous by TLC analysis. 1H NMR (300 MHz) δ4.87 (br s, 1 H), 4.45-4.40 (m, 1 H), 2.22, (m, 1H), 2.02 (s, 3 H), 1.99-1.91 (m, 2 H), 1.82-1.20 (m, 21 H).
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.[Br-:20].[Li+]>CCC(=O)CC>[Br:20][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: [Li+]
Solvent: CCC(=O)CC
Product: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F

Procedure:
A solution of Intermediate 25 (approximately 10 mmol) 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 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: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]1.C[Al](C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:39][C:40]3[C:46](=[O:47])[O:45][CH2:44][CH2:43][C:41]=3[N:42]=2)=[CH:34][CH:33]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:46]([C:40]2[S:39][C:38]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)=[N:42][C:41]=2[CH2:43][CH2:44][OH:45])=[O:47])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]1
Reactant: COc1cc(N)ccc1N1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)ccc1N1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve the above 3-methoxy-4-(4-triisopropylsilanyloxy-piperidin-1-yl)-phenylamine (1.41 g, 3.72 mmol) in CH2Cl2 and add a trimethylaluminum solution (2.0M in hexanes, 2.25 mL, 4.50 mmol). Stir the solution at room temperature for 1 h, then add solid 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (1.01 g, 3.80 mmol) and continue stirring at room temperature overnight. Carefully quench reaction with saturated Rochelle's salt solution (15 mL) and stir at room temperature for 1 h. Extract the mixture with CH2Cl2 (3×20 mL). Combine all organic solutions, dry, filter, and concentrate in vacuo. Purify the crude material by flash chromatography using 2N NH3/MeOH in CH2Cl2 as eluent to give the title compound as a sold (1.00 g, 42%). MS (ES+) 644.0 (M+1)+, (ES−) 642.3 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 10.76 (s, 1H), 8.00 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.8 Hz), 7.35 (d, 1H, J=2.2 Hz), 7.13 (dd, 1H, J=8.8, 2.2 Hz), 6.88 (d, 1H, J=8.8 Hz), 5.78 (t, 1H, J=4.4 Hz), 3.94-3.86 (m, 3H), 3.78 (s, 3H), 3.21-3.13 (m, 4H), 2.78-2.70 (m, 2H), 1.93-1.85 (m, 2H), 1.67-1.57 (m, 2H), 1.06-1.04 (m, 21H).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[CH:3]1Br>O>[CH:22]1[C:4]2[CH2:3][CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:6](=[C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:5]=2[CH:19]=[CH:20][CH:21]=1
Reactant: BrC1c2ccccc2C(=C2CCNCC2)c2ccccc2C1Br
Solvent: O
Product: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1

Procedure:
In accordance with the process of the present invention, the starting material, i.e., the 4-(10,11-dibromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine (I) is treated in an inert polar solvent with hydroxide ion, but preferably by dissolving the salt in water, to produce the biologically active 10,11-dihydroxy derivative of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine (II). The product produced in this manner is biologically active and is a mixture of primarily the cis and trans isomers, the major portion being present in the cis configuration. The cis isomer of the compound may be isolated by selective fractional crystallization.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:15])[OH:14])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[I:21]Cl.O>C(O)(=O)C>[I:21][C:6]1[C:7]2[S:11][C:10]([NH:12][C:13](=[O:14])[OH:15])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2sc(NC(=O)O)nc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(I)c2sc(NC(=O)O)nc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(4-Methoxy-benzothiazol-2-yl)-carbamic acid methyll ester (31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are dissolved in 400 ml of glacial acetic acid and slowly treated with iodine monochloride (13.5 ml, 264 mmol) at 0° C. The reaction mixture is then slowly warmed to room temperature and stirred for 15 hours. After addition of water (1.3 1), the formed precipitate is filtered off and washed with water. The filter cake is then dissolved in a minimal amount of tetrahydrofurane (about 150 ml) and decolorized with 1M aqueous sodium thiosulfate. The product is precipitated by the addition of water (about 2.0 1), filtered off and dried at 60° C. for 12 hours. 42.3 g (89%) white solid. MS: m/e=364 (M+).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8](OC)=[O:9])=[CH:6][N:5]([CH2:12][C:13]#[CH:14])[CH:4]=1)#[N:2].O1CCCC1.[BH4-].[Li+].[Cl-].[Na+]>O>[OH:9][CH2:8][C:7]1[C:3]([C:1]#[N:2])=[CH:4][N:5]([CH2:12][C:13]#[CH:14])[CH:6]=1
Reactant: C#CCn1cc(C#N)c(C(=O)OC)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1cc(C#N)c(CO)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
3.90 g of methyl 3-cyano-1-(2-propynyl)-1H-pyrrole-4-carboxylate, 35 ml of tetrahydrofuran, 11 ml of water and 1.556 g of lithium borohydride were mixed together and stirred for 3 hours 30 minutes at 20° C. The reaction mixture was poured into a saturated aqueous solution of sodium chloride with stirring and was extracted with ethyl acetate. The extracts were concentrated to dryness by distilling under reduced pressure and the residue was chromatographed over silica. Elution with a mixture of hexane and ethyl acetate (4-6) yielded 1.33 g of 4-hydroxymethyl-1-(2-propynyl)-1H-pyrrole-3-carbonitrile melting at 95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:21](Cl)(=O)[CH2:22][CH2:23][CH3:24].C(N(CC)CC)C.Cl.N1C=CC=CC=1>ClCCl.C(O)C>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102 %

Procedure:
A solution of ethyl 4-(3-amino[1,5]naphthyridin-4-ylamino)butanoate (2.0 g, 7.3 mmol) in dichloromethane (35 mL) was cooled to 0° C. Butyryl chloride (0.68 mL, 8.0 mmol) was added dropwise over a period of ten minutes, and the reaction was allowed to warm to ambient temperature, stirred for 90 minutes, and concentrated under reduced pressure. Triethylamine (3.0 mL, 22 mmol) and ethanol (35 mL) were added, and the resulting solution was heated at reflux for two days. Pyridine hydrochloride (0.1 equivalents) was added, and the reaction was heated at reflux overnight. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane (70 mL) and saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was separated and extracted with dichloromethane (2×25 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.43 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoate as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[Br:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:17][CH2:18][CH2:19][O:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: BrCCBr
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccccc1)c1cc(Cl)ccc1OCCBr
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of (5-chloro-2-hydroxy-phenyl)-phenyl-methanone (0.93 g, 4.0 mmol), δ 1,2-dibromoethane (3.5 mL, 40 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in acetonitrile (10 mL) is heated at reflux under N2 over weekend (about 60 hours). After cooling to room temperature, solid potassium bromide is filtered off and washed with ca. 70 mL of acetonitrile. The filtrate is evaporated, and the crude mixture purified by column chromatography (SiO2, 5-12% ethyl acetate in hexanes) to afford 1.18 g (87%) of the title compound as colorless product. APCI-MS: m/z 339 [(M+H)+, 35Cl, 79Br], 341 [(M+H)+, 37Cl, 79Br], 343 [(M+H)+, 37Cl, 81Br]. 1H-NMR (300 MHz; CDCl3): δ7.78 (2H d, 8.1 Hz); 7.58 (1H, br t, 7.5 Hz); 7.38-7.50 (4H, m); 6.92 (1H, d, 8.6 Hz); 4.18 (2H, t; 6.5 Hz); 3.26 (2H, t, 6.5 Hz).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].Br[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:25])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].COC(C1C=C(C=CC=1)CN1C2C(=CC=CC=2)C(=O)NC1=O)=O>>[F:25][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[NH:3][C:2]2=[O:12])=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cc(CBr)ccc1F
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Agent: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Product: COC(=O)c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F

Procedure:
The title compound was prepared from quinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those described for the synthesis of compound of Example 1. 1H NMR (DMSO-d6): 11.75 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.84 (d, J=6.9 Hz, 1H), 7.67-7.55 (m, 2H), 7.32-7.21 (m, 3H), 5.32 (s, 2H), 3.81 (s, 3H). MS: m/z 329.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:12])[CH2:10][CH3:11])[CH2:5][CH2:4]1.[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>>[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:1][CH2:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9](=[O:12])[CH2:10][CH3:11])[CH2:7][CH2:8]2)[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(N)cccc1F
Reactant: CCC(=O)N1CCC(CO)CC1
Product: CCC(=O)N1CCC(COc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22a from 1-(4-(hydroxymethyl)piperidin-1-yl)propan-1-one (Example 153c) and 2-amino-6-fluorobenzonitrile as a pale-yellow solid (15%). MS 288 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH3:7])[CH2:5][OH:6].C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>>[CH3:21][O:22][CH2:23][O:6][CH2:5][C@@H:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8]
Reactant: COC(=O)[C@H](C)CO
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC[C@@H](C)C(=O)OC
Temperature: -78 °C
Yield: 87.2 %

Procedure:
(R)-3-Hydroxy-2-methyl-propionic acid methyl ester (8.60 g, 0.0728 mol) was dissolved in methylene chloride (200 mL, 3 mol), followed by N,N-diisopropylethylamine (25.4 mL, 0.146 mol). The reaction mixture was then cooled to −78° C., and chloromethyl methyl ether (9.48 mL, 0.0874 mol) was added dropwise. The reaction mixture was then allowed to warm up gradually over for 5 hours to 23° C., and quenched with Na2CO3 (sat). Organic layer was separated, and washed with water, brine, and then dried over Na2SO4. The to crude mixture was purified via chromatography (SiO2, 120g, 0-30% ethyl acetate/hexanes) to give 10.3 g clear liquid product (87%). 1H NMR (CHLOROFORM-d) δ: 4.61 (s, 2H), 3.71 (m, 4H), 3.58 (dd, J=9.5, 5.5 Hz, 1H), 3.35 (s, 3H), 2.77 (m, 1H), 1.19 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:27].C[O:29][C:30](=[O:40])[CH:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)O>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([OH:40])=[O:29]
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(O)ccc2c1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1

Procedure:
The title compound was prepared from 1-bromo-6-(2-butyl-benzofuran-3-carbonyl)-naphthalen-2-ol, and 3-phenyllactic methyl ester, in substantially the same manner, as described in Example 5, and was obtained as a white solid, mp 165-167° C.; MS m/e 570 (M+);
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:39][N:37]([CH3:38])[CH2:36][CH2:35][O:34][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]=1[CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:40])=[O:5])(=[O:14])=[O:13]
Reactant: CN(C)CCOc1ccc2ccccc2c1CCOc1ccccc1S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc2ccccc2c1CCOc1ccccc1S(=O)(=O)NC(C=O)CC(=O)O
Yield: 18.2 %

Procedure:
3-(2-{2-[2-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-4-oxo-butyric acid tert-butyl ester (190 mg, 0.33 mmol) was stirred with trifluoroacetic acid (0.4 mL) in CH2Cl2 (1.2 mL) at room temperature for 1 h. Analytical HPLC analysis indicated the reaction was complete. The reaction mixture was concentrated. Residual trifluoroacetic acid was azeotroped with toluene. The crude product was purified by preparative HPLC to give 3-(2-{2-[2-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-4-oxo-butyric acid (31 mg, 0.060 mmol) as a white solid in 18% yield. MS (APCI) m/z 515.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([CH:20]2[CH2:22][CH2:21]2)([OH:8])[C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (518 mg, 1.49 mmol) in anhydrous THF (16 ml) was treated dropwise over 20 min with cyclopropylmagnesium bromide (1.49 mmol, 0.5 M in tetrahydrofuran, 2.99 mL) at 0° C. under a nitrogen atmosphere. After stirring 1 h at room temperature, additional cyclopropylmagnesium bromide (2.23 mmol, 0.5 M in tetrahydrofuran, 4.48 mL) was added dropwise over 20 min at 0° C. and then the mixture was allowed to reach room temperature. After 4 h the mixture was diluted with saturated ammonium chloride and ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 20% EtOAc in hexanes) to afford racemic ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)(cyclopropyl)hydroxymethyl]cyclohexanecarboxylate as a white solid. Two enantiomers were separated by chiral super critical fluid chromatography (Chiral Technology AS, 2.1×25 cm, 10 uM, 45/55 MeOH/CO2, Flow Rate: 70 mL/min, 14 min run time, WL: 220 nm) Elution was observed at 7.91 min and 10.78 min. Pooled fractions of each peak were concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(N=C=O)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: Cc1ccc(C)c(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)c1

Procedure:
87 mg of solid yellow 3-{4-[3-(2,5-dimethylphenyl)ureido]phenyl}-1H-pyrrolo-[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2,5-dimethylphenyl isocyanate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[O:12][N:11]=2)[CH:6]=[C:7](F)[CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.CN(C)C=O>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[O:12][N:11]=2)[CH:6]=[C:7]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH:8]=1)#[N:2]
Reactant: c1c[nH]cn1
Reactant: N#Cc1cc(F)cc(-c2noc(-c3ccccn3)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2noc(-c3ccccn3)n2)cc(-n2ccnc2)c1

Procedure:
In a screw cap vial equipped with stir bar added 3-(3-Cyano-5-fluorophenyl)-5-(2-Pyridyl)-1,2,4-oxadiazole (20 mg, 0.08 mmol), potassium carbonate (20.8 mg, 0.15 mmol), imidazole (7.7 mg, 0.11 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 120° C. for 2 h. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 1% methanol in dichloromethane to isolate the free base of the desired compound as a white solid. The free base was converted to it's hydrochloride salt (11.7 mg), white solid. 1H-NMR (DMSO), δ (ppm): 9.81 (s, 1H), 8.83 (m, 4H), 8.42 (m, 2H), 8.19 (dt, 1H), 7.92 (s, 1H), 7.80 (dd, 1H).
Reaction SMILES: CS(O[C@H:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][C:8]([NH2:10])=[O:9])(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@@H:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][C:8]([NH2:10])=[O:9])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCC[C@H](CC(N)=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)N=[N+]=[N-]
Yield: 51.6 %

Procedure:
A solution of (R)-3-methanesulfonyloxyhexadecanamide (32 mg) and sodium azide (12 mg) in N,N-dimethylformamide (1 ml) was heated at 60° C. for 2 hours. The cooled mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with water (10 ml), and brine (10 ml), dried, and concentrated under vacuum, then the residue was recrystallized at -20° C. from a mixture of ethyl acetate (0.2 ml) and n-hexane (2 ml) to give (S)-3-azidohexadecanamide (14 mg).