Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>CCO>[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
In a method similar to Example A 4,7-dichloroquinoline (0.49 g, 2.0 mmol), 3-(tert-butoxycarbonylamino)pyrrolidine (1.86 g, 10.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.12 g, 10.0 mmol) are heated in EtOH for 15 h at reflux. The reaction mixture is concentrated, diluted with EtOAc, washed with water, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding 245 mg of the product as a colorless solid.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].S(=O)(=O)(O)O.[CH2:14]=[C:15]([CH3:17])[CH3:16]>ClCCl>[C:15]([O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])([CH3:17])([CH3:16])[CH3:14]
Reactant: COC(=O)[C@@H](C)CO
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)[C@@H](C)COC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (2.36 g; 20 mmole) was dissolved in dry dichloromethane (30 ml), conc. sulfuric acid (0.2 ml) was added thereto, and isobutene (23.5 g) was introduced into the resultant mixture kept at -60° to -70° C., followed by stirring at room temperature for 3 hours. The reaction mixture was sealed and stirred overnight, and unreacted isobutene was removed therefrom by distillation. The mixture was washed successively with water and a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl (S)-3-t-butoxy-2-methylpropionate.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:5]([O:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([Cl:3])=[O:31])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCCCCCCCC(=O)OCc1ccccc1

Procedure:
One drop of dimethyl formamide and 2.32 ml of thionyl chloride were added to 3.01 g (8 millimoles) of the 1,14-tetradecane dicarboxylic acid monobenzyl ester obtained in Production Example 4. The reaction mixture was heated and allowed to reflux for one hour. Unreacted thionyl chloride was subsequently removed using distillation under reduced pressure to obtain 3.2 g of 1,14-tetradecane dicarboxylic acid monochloride monobenzyl ester in the form of a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15]2>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18]([CH2:17][C:16]3[C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=4[NH:9][C:15]=32)=[CH:19][CH:20]=1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: Cc1cc(C)cc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c2c3c([nH]c2c1)-c1cc(F)ccc1C3
Temperature: 85 °C

Procedure:
To a solution of 3,5-dimethylphenylhydrazine (2.54 g, 14.7 mmol) and 5-fluoro-1-indanone (2.21 g, 14.7 mmol) in ethanol (24 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Ethanol was removed in vacuo and the resulting orange solid was dissolved in isopropanol (24 mL). Sulfuric acid (36N, 1.65 mL) was added via syringe and the mixture was stirred at reflux (90° C.) for 17 hours and subsequently cooled to room temperature. The solution was basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of a precipitate. The solid was collected by vacuum filtration to yield 47b in 76% crude yield (2.80 g, 11.2 mmol). Crude product was brought on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.32-7.35 (dd, 1H, J=8.2, 5.2 Hz), 0.24-7.26 (m, 1H), 7.01-7.05 (m, 2H), 6.79 (s, 1H), 3.83 (s, 2H), 2.60 (s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.7 (d, J=361.5), 150.0 (d, J=12.0 Hz), 140.9, 140.6, 131.8, 131.2, 128.9, 122.6, 122.3, 121.6 (d, J=4.5 Hz), 117.2 (d, J=13.5 Hz), 113.4 (d, J=25.5 Hz), 113.1 (d, J=25.5 Hz), 109.6, 31.7 (d, J=3.0 Hz), 21.8, 19.3; 19F NMR (CD3CD, 376 MHz): δ −117.9 (m).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>CO.C(N(CC)CC)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: COC(=O)CN
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOP(=O)(Cc1ccccc1CNCC(=O)OC)OCC

Procedure:
A solution of the diethyl[[2(bromomethyl)phenyl]methyl]phosphonate (Example A) (0.9 g, 2.8 mmol) in methanol (25 ml) and triethylamine (5 ml) is treated with glycine methyl ester hydrochloride (0.71 g, 5.6 mmol) and heated at reflux in an oil bath for 19 hours. The solvent is removed in vacuo and the residue dissolved in water and extracted with chloroform. The chloroform layer is dried over magnesium sulfate, filtered, and evaporated. The oily residue is purified via silica gel chromatography (2-4% methanol in chloroform as eluant).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13](=[NH:15])[NH2:14])=[CH:5][CH:4]=1.[O-]CC.[Na+].C([O:30][C:31]([CH:33]=[CH:34][O-])=O)C.[Na+]>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13]2[NH:14][C:31](=[O:30])[CH:33]=[CH:34][N:15]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C=C[O-]
Reactant: N=C(N)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1ccnc(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)[nH]1
Yield: 11.7 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamide hydrochloride (188 mg, 0.515 mmol) in ethanol (8.0 mL) was added 21% sodium ethoxide in ethanol (0.192 mL, 0.515 mmol) and sodium 2-ethoxycarbonyl ethenolate (284 mg, 2.06 mmol) (prepared as in J. Med. Chem., (2001), 44(17), 2695-2700), and the reaction was heated to reflux overnight. The reaction was cooled and concentrated. The residue was slurried DCM (15 mL) and water (15 mL) for 20 minutes. The solids were filtered, dried and purified by silica gel chromatography (methanol/DCM=0/100→15/85) to give the product. HPLC gave 23 mg of the title compound as a yellow solid. (12% yield). LC/MS (FA) ES+ 381. 1H NMR (300 MHz, DMSO-d6) δ: 8.72-8.60 (m, 2H), 8.41 (d, 1H, J=5.7 Hz), 7.88-7.85 (m, 2H), 7.40-7.36 (m, 2H), 7.32-7.28 (m, 2H), 6.58 (d, 1H, J=5.7 Hz), 4.80 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(O)(=[O:39])CCCCCCCCCCCCCCCCC>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[O:39][C@H:7]1[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCC[C@H]1O[C@H]1C/C=C\CCCCCCCC(=O)O

Procedure:
Vernolia oil undergoes saponification and acification followed by cold temperature (-20° C.) crystallization to yield a methylated product comprised of vernolic, palmitic, oleic, linoleic and stearic acid. The vernolic acid is isolated and further purified through a series of low temperature recrystalizations. The purified vernolic acid, ##STR1## is then hydrogenated to yield 12,13-epoxystearic acid, having the formula: ##STR2## The 12,13-epoxystearic acid is then oxidized to yield 12-oxododecanoic acid, ##STR3## By reacting the 12-oxododecanoic acid with hydroxylamine, 12-oxododecanoic acid oxime ##STR4## is formed. The Nylon-12 monomer, 12-aminododecanoic acid:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O.CCOC(C)=O>[N:19]([CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:20]=[N-:21]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CCBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of diethyl 1-(2-bromoethyl)-1H-pyrrole-2,4-dicarboxylate (0.8 g) in DMF (10 mL) was added sodium azide (0.2 g, 3.07 mmol). The resulting mixture was stirred at rt overnight then diluted with water (10 mL) and EtOAc (100 mL). After separation, the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. Purification via flash chromatography (petroleum ether:EtOAc, 20:1 to 15:1) afforded diethyl 1-(2-azidoethyl)-1H-pyrrole-2,4-dicarboxylate (0.4 g, 57%). 1H NMR (CDCl3, 300 MHz) δ7.49 (d, J=1.8 Hz, 1 H), 7.43 (d, J=1.8 Hz, 1 H), 4.88 (t, J=5.5 Hz, 2 H), 4.32 (q, J=7.2 Hz, 4 H), 3.70 (t, J=6.4 Hz, 2 H), 1.38 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccc(Cl)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 4-chlorobenzylamine (45 mg, 0.32 mmol). The title compound was obtained as a yellow solid (18 mg, 14% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.40 (1H, m), 8.99 (2H, s), 8.46 (1H, s), 7.43 (2H, dd), 7.31 (2H, dd), 4.39 (2H, m). MS m/z: 471.97, 473.95 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Temperature: 10 °C
Yield: 79.6 %

Procedure:
The mixture of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (30.74 g, 0.1895 mol), benzyl bromide (27.0 mL, 0.227 mol) and potassium carbonate (39.3 g, 0.284 mol) in acetone (250 mL, 3.4 mol) was heated to reflux under an atmosphere of nitrogen for 3 hours. The mixture was cooled to 10° C. with an ice bath, filtered and washed with small amount of to acetone. The filtrate was concentrated in rotavap. The resulting crystals were collected by filtration and washed with EtOAc-hexane then hexane to give a pale yellow solid product as the first crop. The mother liquid was concentrated in rotavapor and the residue was purified by chromatograph with EtOAc:hexane (0:100 to 20:80) to give the second crop of solid product (38.07 g, 80%). 1H NMR (CHLOROFORM-d) δ: 8.02 (d, J=8.6 Hz, 1H), 7.32-7.51 (m, 5H), 6.91 (dd, J=8.8, 2.3 Hz, 1H), 6.80 (s, 1H), 5.13 (s, 2H), 2.93 (t, J=6.1 Hz, 2H), 2.56-2.68 (m, 2H), 2.12 (quin, J=6.3 Hz, 2H). MS (M+1): 253.0.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][CH2:7][CH2:8]2)[O:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Li+].[OH-]>C1C=CC=CC=1.O.CCN(CC)CC>[OH:1][C@@H:2]1[C@H:9]2[C@H:5]([O:6][CH2:7][CH2:8]2)[O:4][CH2:3]1
Reactant: O[C@@H]1CO[C@H]2OCC[C@H]21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a stirred solution of alcohol (5) (400 mg, 3.07 mmol), triphenylphosphine (1.6 g, 61.4 mmol), and p-nitrobenzoic acid (770 mg, 4.61 mmol) in dry benzene (30 mL) at 23° C. was added diisoproylazodicarboxylate (DIAD, 1.2 mL, 6.14 mmol) dropwise. After 1.5 hours, the mixture was concentrated in vacuo, and the crude ester was dissolved in a (4:3:1) mixture of MeOH:Et3N:H2O (24 mL), then treated with LiOH (450 mg, 10.7 mmol). The solution was stirred at room temperature for 2 h. The mixture then was concentrated under reduced pressure and the residue was chromatographed over silica gel to provide the bis-THF (I) (326 mg, 82%); [α]25D −12.4 (c 1.16, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([C:18]#[N:19])[CH:5]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]#[N:19])[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH:9]=1)=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3-Cyano-4-(trifluoromethanesulfonyloxy)-benzoic acid methyl ester from step 1 (2.5 g, 8.1 mmol) and phenylboronic acid (2 g, 16.2 mmol) were dissolved in DMF (33 ml) and treated with Et3N (3.1 ml, 17.8 mmol). Argon was bubbled into the solution for 20 min. and then a catalytic amount of PdCl2 (PPh3)2 (285 mg, 0.405 mmol) was added. The reaction mixture was warmed to 90° C. and stirred for 3 hours under argon atmosphere. The reaction was quenched with satd. NaHCO3 (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:16]3[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH:17]=3)[CH:7]=[CH:8][C:9]=2[N+:13]([O-])=O)[NH:4][CH:3]=1.Cl[Sn]Cl>CCO>[NH2:13][C:9]1[CH:8]=[CH:7][C:6]([C:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH:17]=2)=[C:5]2[C:10]=1[C:11](=[O:12])[C:2]([CH3:1])=[CH:3][NH:4]2
Reactant: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c(=O)c(C)c[nH]c23)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)C1CC=C(c2ccc(N)c3c(=O)c(C)c[nH]c23)CC1
Yield: 48.9 %

Procedure:
A solution of ethyl 4-(3-methyl-5-nitro-4-oxo-1,4-dihydroquinolin-8-yl)cyclohex-3-ene-1-carboxylate (Compound 304D, 600 mg, 1.69 mmol) in EtOH (50 mL) was charged with SnCl2 (1.2 g, 5.33 mmol). The resulting mixture was stirred under reflux for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was quenched with aq. NaHCO3 solution (500 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The material was purified by prep TLC to afford the desired compound (270 mg, yield: 49%). 1H NMR (CDCl3, 400 MHz): δ=1.22 (t, J=7.2 Hz, 3 H), 1.99 (s, 3 H), 2.03 (m, 1 H), 2.11-2.13 (m, 2 H), 2.19-2.21 (m, 2 H), 2.34-2.39 (m, 2 H), 2.78 (m, 1 H), 3.42 (d, J=3.2 Hz, 1 H), 4.12 (q, J=7.2 Hz, 2 H), 5.71 (s, 1 H), 6.20 (d, J=8.0 Hz, 1 H), 6.71 (s, br, 2 H), 6.93 (d, J=8.0 Hz, 1 H), 7.36 (d, J=6.0 Hz, 1 H), 8.91 (s, br, 1 H).
Reaction SMILES: CO.C(Cl)Cl.[CH2:6]([O:8][C:9](=[O:37])[C@@H:10]([NH:29]C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[N:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[CH3:7]>C(OC(O)C)C>[C:19]1([NH:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH2:29])[C:9]([O:8][CH2:6][CH3:7])=[O:37])=[CH:17][CH:16]=2)[C:28]2[C:23](=[CH:24][CH:25]=[N:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(C)O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](N)Cc1ccc(Nc2nccc3ccncc23)cc1

Procedure:
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino] propanoate (638 mg, 2.07 mmol) and Intermediate 3 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120° for 15 min and at 100° for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl) amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (silica; 10% MeOH/DCM) afforded the title compound as a straw-colored solid (420 mg, 60% over two steps). δH (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[NH3:26]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](=[O:19])[NH2:26])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Reactant: N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2sc(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (570 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the solution was mixed with 1,1-carbonyldiimidazole (320 mg, 2.0 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with ammonia dioxane solution (0.5 M, 8.0 ml, 4.0 mmol) and the stirring was continued for 16 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the residue was mixed with ethyl acetate and washed with water, hydrochloric acid (1 N), sodium hydroxide aqueous solution (1 N) and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under a reduced pressure to obtain 450 mg (1.6 mmol, 80% in yield) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[O:23][C:22]([C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)=[O:25])=[N:21][N:20]=1.C(N(CC)CC)C>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[O:23][C:22]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:35][CH2:34]3)=[N:29][CH:28]=2)=[O:25])=[N:21][N:20]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(C(=O)Oc3ccccc3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 2 h
Yield: 30.6 %

Procedure:
Phenyl chloroformate (0.036 mL, 0.29 mmol) was added to a mixture of 5-[(2-fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41, 100 mg, 0.26 mmol) and triethylamine (0.07 mL, 0.52 mmol) in DMF (1.5 mL). The mixture was stirred for 2 h then directly purified by reverse phase HPLC eluting with a gradient of acetonitrile/water containing 0.2% TFA to give the title compound (40 mg, 31%) as a solid; 1H NMR δ 10.95 (1H, s), 10.73 (1H, s), 8.50 (1H, s), 8.05-7.95 (2H, m), 7.45-7.10 (8H, m), 6.90 (1H, d), 3.80-3.60 (8H, m); MS m/e MH+ 504.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)[CH2:7][CH2:8][CH3:9])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC[C@@H](CC(=O)OCC)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-(2-Nitro-phenylamino)-hexanoic acid ethyl ester (795 mg, 2.8 mmol) in EtOH (20 mL) was added Pd/C (10% wt on carbon) (300 mg). The solution was stirred at room temperature for 3 hours. The solution was filtered and the filtrate was concentrated. The residue (683 mg, 96%) was used in the next step of the synthesis without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[N:14][C:13]([Cl:18])=[CH:12][N:11]=1.N1C=CC=CC=1.Cl>ClCCl>[Cl:18][C:13]1[N:14]=[C:15]([O:16][CH3:17])[C:10]([NH:9][C:2](=[O:3])[O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[N:11][CH:12]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(Cl)cnc1NC(=O)OCC(C)C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
Isobutyl chloroformate (4.1 g) was added to a solution of 2-amino-5-chloro-3-methoxypyrazine (4.8 g) and pyridine (2.37 g) in dichloromethane (50 ml). The solution was left to stand for 20 hours and then two further portions of isobutyl chloroformate (1.02 g) and pyridine (0.59 g) were added at 2 hour intervals. 2M hydrochloric acid (25 ml) was added and the organic layer was separated. The solution was washed with 2M hydrochloric acid (2×25 ml), water (25 ml) and saturated sodium chloride solution (25 ml) The solution was dried (MgSO4) and volatile material was removed by evaporation. The residue was recrystallised from isohexane to give isobutyl N-(5-chloro-3-methoxypyrazin-2-yl)carbamate (6.15 g), m.p. 90°-91° C.; microanalysis found: C, 46.3; H, 5.5; N, 16.4%; C10H14C1N3O3 requires: C, 46.3; H, 5.4; N, 16.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:14]([C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CCC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(CCC(C)=O)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a stirred mixture of 4-(4-methoxyphenyl)-2-butanone (15.4 g.), benzoyl chloride (13 g.) and methylene chloride (250 ml) at 0° C. was added portionwise aluminium chloride (23 g.) over a 20 minute period. The mixture was stirred a further 1 hour at room temperature and then poured onto ice and worked up in the usual way. Distillation of the product gave 4-(3-benzoyl-4-methoxyphenyl)-2-butanone (12 g.), b.p. 188°-192° C. (0.01 mm).