Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:11])=[C:3]([F:10])[CH:4]=1
Reactant: COc1ccc(Br)c(F)c1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2C)c(F)c1

Procedure:
A mixture of 4-bromo-3-fluoroanisole, 2-methylphenyl boronic acid, tetrakis(triphenylphosphine) palladium (5% mol) and sodium carbonate (0.23 g, 2.1 mmol) in 20 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 5 h. TLC (EtOAc:hexane/2:98) showed that the reaction was over. The solvents was removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×50 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after purification with preparative TLC using 2% EtOAc in hexane as the eluant.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Reactant: [H][H]
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Reaction time: 16 h

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4 -acetate, 5.63 g (0.048 mol), in 100 mL of methanol saturated with gaseous ammonia is treated with 0.5 g of Raney nickel #30 and hydrogen gas in a shaker at 50 psi and 40 ° C. After 16 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to give 4.93 g of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil with acceptable IR, NMR, C-NMR and MS spectra.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CC(C)=O>[C:6]([C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:17][CH2:16]1)#[N:7]
Reactant: CCOC(=O)CC#N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C#N)CC1

Procedure:
Ethylcyanoacetate (15.0 mL, 141 mmol) was added to a mixture of potassium carbonate (48.7 g, 353 mmol) and acetone (200 mL), and 1,2-dibromoethane (13.4 mL, 155 mmol) was added dropwise to the resulting mixture over a period of eight minutes. The reaction was heated at reflux overnight. An analysis by TLC indicated the presence of ethylcyanoacetate, and additional 1,2-dibromoethane (1.8 mL, 0.15 equivalent) was added. The reaction mixture was heated at reflux for an additional four hours and filtered through a layer of CELITE filter agent. The filter cake was washed with acetone (200 mL), and the combined filtrates were concentrated under reduced pressure to provide ethyl 1-cyanocyclopropanecarboxylate as an orange oil containing about 10 mole % 1,2-dibromoethane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
m-Nitrobenzoic acid (11.2 g, 67.0 mmol) was taken up in sulfuric acid (30 mL) and heated to 60° C. To this solution was added N-bromosuccinimide (14.3 g, 80.4 mmol) in three portions each over a 15 minute period. After stirring for 2 h, the mixture was poured into crushed ice (100 g) to precipitate a solid. The solid was filtered, washed with water followed by hexanes to give the desired product (16 g, 97%). LCMS for C7H3BrNO4 (M−H)+: m/z=244.0, 246.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]#[N:17])[C:10]=2[CH:9]=[CH:8]1.[OH-].[Na+]>O1CCCC1>[NH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:16][NH2:17])[C:10]=2[CH:9]=[CH:8]1
Reactant: N#Cc1cccc2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2[nH]ccc12
Yield: 80.8 %

Procedure:
Lithium aluminum hydride (3.80 g, 100.0 mmol) was added in 0.5 g portions over 30 min to a solution of 1H-indole-4-carbonitrile (prepared according to Clark, Robin D.; Repke, David B. J. Heterocycl. Chem. 1985, 22, 121-5; 7.50 g, 52.8 mmol) in tetrahydrofuran (250 mL). The mixture was heated at reflux for 30 min. A solution of 1 M sodium hydroxide was added to quench excess lithium aluminum hydride. The mixture was filtered and the filter cake was washed with water. The filtrate was first made acidic with 1 N HCl and then made basic again by the addition of saturated aqueous NaHCO3. The water layer was then extracted with nBuOH. Evaporation of nBuOH, and drying under vacuum gave 1H-indole-4-methanamine (6.24 g, 80%) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>CCN(CC)CC>[F:8][C:4]1[N:3]=[C:2]([NH:1][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(F)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(F)n1

Procedure:
A solution of 2-amino-6-fluoropyridine (4.2 g) in CH2C2 (100 ml) was treated with Et3N (8 ml) and pivaloyl chloride (5 ml) at 0° C. to room temperature overnight. The reaction mixture was washed with water (50 ml), 2N H2SO4 (50 ml), water (50 ml) and dried (Na2SO4). Evaporation of the solvent afforded 6-fluoro-2-pivaloylaminopyridine (6 g).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][C:11]1=[O:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:38]([C:40]1[C:56]([F:57])=[CH:55][C:43]([O:44][C:45]2[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=2[F:54])=[C:42]([O:58][CH3:59])[CH:41]=1)[CH3:39].C(=O)([O-])O.[Na+]>ClCCl>[CH2:38]([C:40]1[C:56]([F:57])=[CH:55][C:43]([O:44][C:45]2[CH:53]=[CH:52][C:48]([C:49]([N:13]3[CH2:14][CH2:15][NH:10][C:11](=[O:16])[CH2:12]3)=[O:50])=[CH:47][C:46]=2[F:54])=[C:42]([O:58][CH3:59])[CH:41]=1)[CH3:39]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Reactant: O=C1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (2.8 mL, 16 mmol), piperazin-2-one (780 mg, 7.8 mmol), EDCI (1.5 g, 7.8 mmol) and HOBt (1.05 g, 7.8 mmol) were successively added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 2.0 g, 6.5 mmol) in dichloromethane (22 mL). The reaction mixture was stirred at room temperature overnight and then diluted by addition of dichloromethane (50 mL) and a saturated solution of sodium hydrogen carbonate (50 mL). After separation, the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/petroleum ether (80/20) to dichloromethane (100%) to dichloromethane/methanol (98:2 to 95:5) as eluent. The title product was obtained as a yellow solid (2.0 g, 80%).
Reaction SMILES: [CH:1]1([N:6]([C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=2)[CH2:7][CH2:8][C:9](OC)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[Cl-]>[Fe].CCO.O>[Cl:22][C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[N:14]=1
Reactant: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Yield: 43.7 %

Procedure:
Methyl 3-[cyclopentyl(2-chloro-5-nitropyrimidin-4-yl)amino]propanoate (1.0 g, 0.003 mol, 1 eq) and NH4Cl (1.38 g, 0.025 mol, 8.5 eq) were added to EtOH/H2O (4:1, 10 mL) and the mixture heated to reflux. Iron powder (1.36 g, 0.024 mol, 8 eq) was added portionwise and after 2 h the RM was hot filtered through celite washing through with EtOAc (10 mL) and EtOH (10 mL) [both hot]. The solvent was evaporated under reduced pressure to give the product as a brown solid (0.35 g, 43%); 1H (DMSO-d6): δ 1.55 (4H, m, 2CH2), 1.7 (2H, m, CH2), 1.83 (2H, m, CH2), 2.66 (2H, t, J=5 Hz, CH2), 3.57 (2H, t, J=5 Hz, CH2), 5.01 (1H, m, CH), 7.83 (1H, s, CH), 9.71 (1H, s, NH); MS+ve: 267.2; Rt=2.87 min (Analytical—1).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(=O)CC1
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of 4,4-dimethyl-2-cyclohexen-1-one (25.37 g, 0.204 mol) in ethanol at room temperature (200 mL) was treated with 10% Pd/C catalyst (1.5 g) and agitated under 60 psi H2 for 4 hours. The reaction was filtered and the filter cake was washed with ethanol. The filtrate was concentrated to provide the desired product (22.4 g, 87%). MS (CI) m/e 127 (M+H)+.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CSc1ncc2ncnc(O)c2n1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1
Temperature: 100 °C

Procedure:
148 g of 4-hydroxy-6-methylthiopyrimido[5,4-d]pyrimidine, 286 ml of hexamethyldisilazane, 333 g of 3-chloro-4-fluoroaniline and 15 g of p-toluenesulphonic acid are heated at 140° C. for 23 hours. The reaction mixture is cooled and, after addition of 4 l of methanol, heated at 100° C. for one hour. The methanol is distilled off and the residue is triturated three times with diethyl ether and filtered off with suction.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].NC1C2C=C([N+]([O-])=O)C=CC=2SN=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C=O)C>[C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1nsc2ccc([N+](=O)[O-])cc12
Agent: Nc1nsc2ccc([N+](=O)[O-])cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C(C)=O)c1nsc2ccc(N)cc12
Reaction time: 4 h

Procedure:
N-acetyl-N-(5-nitro-benzo[d]isothiazol-3-yl)-acetamide (KRB01049): To a solution of 3-amino-5-nitrobenzisothiazole (1.00 g, 5.12 mmol) in DMF (20 mL) was added acetic anhydride (1 mL) and triethylamine (1 mL) and the resulting solution was stirred for 4 h. The yellow precipitate was filtered, washed quickly with cold ethyl acetate, and dried in vacuo (1.139 g, 80%). 1H NMR (CDCl3): δ 9.20 (1H, d, J=2.5 Hz), 8.87 (1H, d, J=9.4 Hz), 8.55 (1H, dd, J=9.4, 2.5 Hz), 2.69 (3H, s), 2.63 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Na+].[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][C:32]([O-])=[O:33])[CH3:29].O.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>C1(C)C=CC=CC=1>[C:38]1([CH3:48])[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1.[CH2:28]([N:30]([CH2:31][C:32]([O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[O:33])[CH2:35][CH3:36])[CH3:29]
Reactant: CCN(CC)CC(=O)[O-]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)CC(=O)OC1CCN(c2ccc(/C=C(\C#N)c3ccc(OC)c(OC)c3)s2)CC1
Yield: 27.9 %

Procedure:
Compound 6 (480 mg) was dissolved in toluene (100 mL), and N,N-diethylglycin sodium salt (296 mg) and p-toluenesulfonic acid monohydrate (490 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 237 mg, 37.7%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](O)=[O:7])#[N:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)C(C)C)(C)C.P(C#N)(OCC)(OCC)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:18]([O:19][CH3:20])[CH3:17])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNOC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of 3-cyano-5-(trifluoromethyl)benzoic acid (200 mg, 0.93 mmol) in tetrahydrofuran (2 mL) stirred on an ice bath was added N,O-dimethylhydroxyamine hydrochloride (145 mg, 1.49 mmol), N,N-diisopropylethylamine (470 mg, 3.64 mmol) and diethyl cyanophosphate (DEPC, 227 mg, 1.39 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with 1 M hydrochloric acid (0.5 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-cyano-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (196 mg, 82%) as a pale yellow solid.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].OCC1(CC2C=CC=CC=2O)CCCCC1>>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1
Reactant: O=C1CCSc2ccccc21
Agent: OCC1(Cc2ccccc2O)CCCCC1
Agent: [Al+3]
Agent: [H-]
Product: OC1CCSc2ccccc21

Procedure:
Reduction of thiochroman-4-one with lithium aluminum hydride by the method of Preparation O, Part (iii), affords thiochroman-4-ol in like manner. This is taken up in acetic acid containing a molar excess of acetic anhydride, the mixture heated at reflux for three hours, cooled, ethanol added to quench the excess anhydride and the mixture hydrogenated by the method of Example 11.
Reaction SMILES: B.[F:2][C:3]([F:11])([F:10])[C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1.[ClH:12]>C1COCC1>[ClH:12].[F:2][C:3]([F:11])([F:10])[C:4]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5]1
Reactant: N#CCC1(C(F)(F)F)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCCC1(C(F)(F)F)CC1
Temperature: 70 °C
Yield: 40 %

Procedure:
Add borane (10 M in dimethylsulfide, 3 mL, 30 mmol) to a solution of 2-(1-(trifluoromethyl)cyclopropyl)acetonitrile (2.2 g, 14.7 mmol) in THF (60 mL), under N2, and heat at 70° C. overnight. Cool to 0° C., add methanolic HCl drop-wise, concentrate to dryness, co-evaporate with MeOH, add EtOAc, collect the solids via filtration and dry to afford the title compound (1.1 g, 40%). 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 3H), 2.87 (t, J=8.4 Hz, 2H), 1.90-1.86 (m, 2H), 0.96-0.93 (m, 2H), 0.82-0.81 (m, 2H).
Reaction SMILES: II.C(N(CC)CC)C.[CH2:10]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][C:22](=[O:29])[NH:23][CH2:24][C:25](=O)[CH2:26][CH3:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][C:22]1[O:29][C:25]([CH2:26][CH3:27])=[CH:24][N:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of polymer supported triphenylphosphene (19.6 g, 58.9 mmol) in DCM (250 ml) is added iodine (14.95 g, 58.9 mmol). After stirring at room temperature for 10 minutes, the mixture is treated with triethylamine (16.4 ml, 117.5 mmol) followed by a solution of [2-(2-oxo-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 2) (6.88 g, 23.5 mmol) in DCM (50 ml). The reaction mixture is stirred overnight and then filtered through celite, washed through with DCM (500 ml) and the solvent removed in vacuo to yield the titled compound as a brown solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]([CH3:15])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH3:14][O:13][C:10]1[C:9]([CH3:15])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[C:11]=1[CH3:12]
Reactant: COc1c(C)cnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cnc(CO)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
94.9 g of (4-methoxy-3,5-dimethyl-2-pyridyl)methyl acetate were dissolved in 570 ml of ethanol. 285 ml of 3N sodium hydroxide solution were then added dropwise thereto at 0° and the mixture was stirred at room temperature for 3 hours. The ethanol was subsequently removed in vacuo, whereupon the residual aqueous solution was extracted three times with 300 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo The residue was crystallized from petroleum ether and there was obtained 4-methoxy-3,5-dimethyl-2-pyridylmethanol of melting point 49-51° .
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[Cl:16][S:17]([C:14]1[CH:13]=[CH:12][C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([CH2:1][CH3:2])[CH:15]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)COc1ccccc1CC
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC
Temperature: 0 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a 250ml round-bottom flask containing chlorosulfonic acid (30ml) cooled to 0° C. was added ethyl (2-ethylphenoxy)acetate (7.2g, 34.6mmoles) dropwise. Once the addition was complete the ice-bath was removed and the reaction was allowed to warm to room temperature at which the reaction was stirred for 3hours. The reaction was then slowly added to ice and, once the excess chlorosulfonic acid was quenched, the mixture was diluted with CH2Cl2(200ml). The phases were separated and the aqueous fraction washed with CH2Cl2twice. The combined organic fractions were dried over Na2SO4and filtered and concentrated in vacuo to yield 7.2g (70%) of crude product. The crude product was used with no purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]=O)[CH:7]=[N:6]2.COF.ClCCCl.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[BH4-].[Na+]>>[CH:24]1([NH:30][CH2:15][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: COc1cc2ncc(C=O)nc2cc1OC
Agent: COF
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc2ncc(CNC3CCCCC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.067 M solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde in 2:1 MeOF/1,2-dichloroethane (7.5 mL, 0.5 mmol) is added cyclohexylamine (0.11 mL, 0.9 mmol). The reaction is allowed to stir at room temperature overnight, then NaBH4 (0.038 g, 1 mmol) is added and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (50% EtOAc/hexanes-approximately 5% MeOH in 50% EtOAc/hexanes). The oil is dissolved in EtOAc/hexanes and treated with HCl in EtOH. The resulting solution is concentrated and the solids are triturated with isopropanol to provide a white solid after drying in vacuo at 60° C. (m.p. 185-190° C., dec.). Anal. Calcd. for C17H23N3O2.HCl: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88; N, 12.07.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:9]1)=[O:7].[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:46]=1.C(OCC)(=O)C>CO.ClCCl>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]1.[Cl:20][C:15]1[CH:14]=[C:13]([C@@:10]2([CH2:21][CH2:22][N:54]3[CH2:53][CH2:52][C:51]([C:47]4[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2cccnc2)CCNCC1
Agent: CN1CCN(C(N)=O)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid 4-methylpiperazine-amide to give, after chromatography on silica gel eluting sequentially with ethyl acetate, 1% methanol/dichloromethane, 3% methanol/dichloromethane, 5% methanol/dichloromethane, 7% methanol/dichloromethane, and then 9% methanol/dichloromethane, the title compound: Rf =0.29 (silica gel, methanol/dichloromethane/concentrated ammonia 10/90/0.5).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[NH3:10].CO>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:10]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: N
Solvent: CO
Product: Nc1cc(Cl)nnc1Cl
Temperature: 25 °C
Yield: 32 %

Procedure:
A MW vial was charged with 3,4,6-trichloropyridazine (5 g, 27.3 mmol) and 7N NH3 in MeOH (19.47 mL, 136 mmol). The MW vial was sealed and the resulting mixture was submitted to MW irradiation at 100° C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 35-60%) to afford the title product (1.49 g, 8.63 mmol, 32% yield) as yellow solid. tR: 1.61 min (HPLC 1); tR: 0.45 min (LC-MS 2); ESI-MS: 163 [M+H]+ (LC-MS 2); Rf=0.40 (hexane/EtOAc 1:1).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>CCOCC>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:17][CH2:6][CH2:7][N:8]=2)=[CH:15][CH:14]=1
Reactant: O=C(NCCO)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Oc1ccc(C2=NCCO2)cc1
Yield: 118 %

Procedure:
Thionyl chloride (160 ml) was added to 40 g of N-(2-hydroxyethyl)-4-hydroxybenzamide with evolution of gas. The reaction mixture was ultrasonicated for 1.75 hours, then cooled and diluted with ether. The resulting solid product was collected by filtration, washed with ether and dried overnight in a vacuum oven at 40° C. to give 42.5 g of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole in the form of its hydrochloride salt.