Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].Cl[CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[F:10][C:11]1[C:12](=[O:45])[NH:13][C:14](=[O:44])[N:15]([CH:43]=1)[C@@H:16]1[O:42][C@H:20]([CH2:21][O:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:18]([OH:19])[CH2:17]1>O1CCOCC1>[F:10][C:11]1[C:12](=[O:45])[NH:13][C:14](=[O:44])[N:15]([CH:43]=1)[C@@H:16]1[O:42][C@H:20]([CH2:21][OH:22])[C@@H:18]([O:19][CH2:4][C:5]2[O:6][CH:7]=[CH:8][CH:9]=2)[CH2:17]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: ClCc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccco3)[C@@H](CO)O2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A 0.35 g quantity of particulate potassium hydroxide and 0.29 g of 2-chloromethylfuran were added to a solution of 1.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 30 ml of dioxane. The mixture was stirred at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed with water and dried. The residue was dissolved in 15 ml of 80% acetic acid and the solution was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in ml of ethyl acetate. The solution was washed with water and dried. The residue was treated with chloroform, the insolubles were filtered and recrystallized from ethanol, giving 0.37 g of 2'-deoxy-5-fluoro-3'-O-(2-furanylmethyl)uridine in a yield of 55%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>[Zn]>[C:11]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Cl)cc1N
Agent: [Zn]
Product: COc1ccc(Cl)cc1NC(C)=O

Procedure:
0.2 mol (31.5 g) of 2-amino-4-chloroanisole, 40 ml of absolute alcohol, 20 ml of acetic anhydride and a pinch of zinc powder are placed in a 150 ml flask; the solution is brought to reflux for 30 minutes. The reaction liquid is poured onto crushed ice. The product obtained is separated; it is crystallized in a methanol/water mixture (20/80).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].CSC.C[OH:18]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=[O:18])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: C=CCc1ccc(C#N)c(OC)c1
Reactant: CO
Solvent: CSC
Product: COc1cc(CC=O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 25 mL flask containing a stir bar was added compound 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile (0.150 g, 0.866 mmol) and MeOH (8 mL). The flask was placed in a cold bath of −78° C. Ozone was bubbled through the flask for about 10 min. followed by addition of dimethyl sulfide (1.5 mL, 0.024 mmol). The flask was taken out of the cold bath and stirred at room temperature for 1 h; LC indicated completion of the reaction. The reaction mixture was concentrated to dryness to give 2-(methyloxy)-4-(2-oxoethyl)benzonitrile.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].Cl.[CH3:6][C:7]1([CH3:15])[CH2:12][O:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1>O>[N:1]([N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][O:11][CH2:12][C:7]1([CH3:15])[CH3:6])=[O:3]
Reactant: CC1(C)COCC(C)(C)N1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)COCC(C)(C)N1N=O
Temperature: 80 °C

Procedure:
15.6 g of sodium nitrite are added to a solution of 27 g of 3,3,5,5-tetramethylmorpholine hydrochloride (prepared in accordance with Synthesis (1984), 122) in 80 ml of water and the mixture is heated at 80° C. for 3 hours. After cooling, the nitroso compound is extracted with diethyl ether. After drying and concentration of the ether phase, 22.2 g of the compound crystallize out. Melting point: 47° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=1)[C:27](O)=[O:28]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:27]([C:26]3[CH:30]=[CH:31][N:32]=[C:24]([OH:23])[CH:25]=3)=[O:28])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)c1ccnc(O)c1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3ccnc(O)c3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-hydroxyisonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.41 (m, 1H), 1.52-1.74 (m, 4H), 1.81 (m, 1H), 3.22 (m, 1H), 3.43 (m, 1H), 4.19 (dd, 1H, J=10.1, 3.8 Hz), 4.62 (t, 1H, J=10.5 Hz), 5.16 (m, 1H), 6.06 (d, 1H, J=7.0 Hz), 6.23 (s, 1H), 6.61 (d, 1H, J=8.0 Hz), 6.87 (d, 1H, J=8.7 Hz), 7.45 (m, 2H), 7.75 (br s, 1H), 8.36 (br s, 1H), 10.92 (s, 1H), 11.73 (br s, 1H). MS 432 (MH+).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15](O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:18]1([CH3:28])C=CC(S(Cl)(=O)=O)=CC=1.Cl/C(=C\C)/[C:31]#[N:32]>C(N(CC)CC)C>[CH3:18][C:28]1[C:15]([C:31]#[N:32])=[C:10]2[N:9]([C:1]=1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C/C=C(\Cl)C#N
Reactant: O=C(O)C1CCCCN1C(=O)c1cccnc1
Solvent: CCN(CC)CC
Product: Cc1c(C#N)c2n(c1-c1cccnc1)CCCC2

Procedure:
2-Methyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile is prepared as described in Example 1, from 11.7 g of N-nicotinoyl piperidine-2-carboxylic acid (prepared according to European Patent Application EP 118321), 10 g of paratoluenesulphonyl chloride, from 24.6 cm3 of triethylamine and from 4.8 cm3 of 2-chlorocrotononitrile. 4.3 g of 2-methyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of a white powder melting at 125° C. 1.7 g of a 70/30 mixture of this compound and of its regioisomer, 1-methyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are also obtained.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([S:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[C:13]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:6]1.Cl>O.O1CCCC1>[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([S:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:13]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:6]1
Reactant: COC(=O)CCCSc1c(Cc2cccc3ccccc23)sc2c(CC(C)C)nn(C)c(=O)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCC(=O)O)c(Cc3cccc4ccccc34)sc12
Reaction time: 48 h
Yield: 25.7 %

Procedure:
A solution of lithium hydroxide hydrate (0.035 g) in water (1 ml) was added to a solution of methyl 4-{[4,5-dihydro-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-4-oxothieno[2,3-d]pyridazin-3-yl]thio}butanoate (0.20 g) in tetrahydrofuran (6 ml) at room temperature. After 2 days, 1M hydrochloric acid (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic extracts were washed with brine, dried, filtered and evaporated. The residue was dissolved in ethyl acetate:isohexane (1:2) and the precipitated solid was collected. The solid was suspended in boiling ethyl acetate (20 ml), cooled and collected to give the title compound (0.05 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>C(O)CC(C)C.CO>[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Reactant: COc1ccc2nc(Cl)nc(Nc3ccccc3)c2c1
Solvent: CC(C)CCO
Solvent: CO
Product: CNS(=O)(=O)Cc1ccc(Nc2nc(Nc3ccccc3)c3cc(OC)ccc3n2)cc1

Procedure:
A solution of 2-chloro-6-methoxy-4-phenylamino-quinazoline (1.15 g) and N-methyl-(4-aminophenyl)-methanesulfonamide (prepared as described in Tetrahedron Letters 1992, 33 8011) (0.89 g) in 5 mL of isopentylalcohol is stirred under nitrogen at 180° C. for 20 min in a sealed vessel. The warm reaction mixture is diluted with methanol and the hydrochloride salt, which is crystallizing on cooling, is filtered off. The crude product is redissolved in ethylacetate and aqueous sodium carbonate solution and extracted with ethylacetate. The organic extracts are dried and evaporated and the solid residue is titurated with diethylether to give N-methyl-[4-(6-methoxy-4-phenylamino-quinazolin-2-ylamino)-phenyl]-methanesulfonamide as light yellow crystals melting at 212-215° C.; (Rf (A2) 0.16. Recrystallisation from methanolic hydrogen chloride and diethylether yields N-methyl-[4-(6-methoxy-4-phenylamino-quinazolin-2-ylamino)-phenyl]-methanesulfonamide hydrochloride as light yellow crystals melting at 264-268° C.; Rf (A2) 0.16, FAB-MS: (M+H)+=450. Analytical data: C23H23N5O3S+HCl.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O[Li:33].O>>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13].[Li+:33]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(C(F)(F)F)c2)cc1
Reactant: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCCN1Cc1cccc(C(F)(F)F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E15) (57 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D32) (69 mg). (LiOH H2O: 1.5 eq; reaction time: 24 hrs)
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.Cl.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19])([O-:14])=[O:13].C(N(CC)CC)C>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:7]=1[NH2:8]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Nc1nc(Cl)c(N)c(NCc2cccc([N+](=O)[O-])c2)n1
Yield: 78.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine-2,5-diamine (700 mg, 3.91 mmol), 3-nitrobenzylamine hydrochloride (885 mg, 4.69 mmol) and triethylamine (1.6 mL, 11.7 mmol) in n-BuOH (20 mL) was refluxed for 17 h, concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and H2O (5 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as an orange solid (906 mg, 76%) which was used in the next reaction without further purification; NMR δH (400 MHz, CDCl3) 8.16 (1H, s), 8.10 (1H, d, J 8.0 Hz), 7.80 (1H, d, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.25 (1H, t, J 6.0 Hz), 5.69 (2H, s), 4.67 (2H, d, J 6.0 Hz) and 3.93 (2H, br s).
Reaction SMILES: [F:1][C:2]1[C:12]([CH3:13])=[C:11](F)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].C1(C)C=CC=CC=1.O>CS(C)=O>[N:15]([C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[C:12]=1[CH3:13])=[N+:16]=[N-:17]
Reactant: CCOC(=O)c1ccc(F)c(C)c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=[N+]=[N-])c(C)c1F
Temperature: 25 °C
Yield: 42.4 %

Procedure:
In 47 ml of dimethyl sulfoxide was dissolved 4.65 g of ethyl 2,4-difluoro-3-methylbenzoate, followed by adding thereto 3.32 g of sodium azide, and the resulting mixture was stirred at 70° C. for 20 hours. The reaction mixture was cooled to room temperature and then added to a mixed solvent of 150 ml of toluene and 150 ml of water, and the organic layer was separated. The organic layer obtained was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent: toluene) to obtain 2.20 g of ethyl 4-azido-2-fluoro-3-methylbenzoate as a light-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc2ncccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-hydroxyquinoline (5.1 g) in pyridine (100 ml) was added acetic anhydride (4.0 ml) and then the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated. The residue was diluted with water. The diluted solution was extracted with ethyl acetate. The extracted solution was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and then concentrated. The residue was azeotropled with toluene to give the title compound (7.7 g) having the following physical data. The obtained compound was used without purification in the subsequent reaction.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C@H:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[N:22]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)[N:24]=3)[CH2:16]1)[CH3:14].C(N(CC)CC)C.[C:55](O)(=[O:59])[C@H:56]([CH3:58])[OH:57].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:25]2[N:24]=[C:23]3[C:28]([N:29]=[C:21]([N:17]4[CH2:18][CH2:19][N:20]([C:55](=[O:59])[C@@H:56]([OH:57])[CH3:58])[C@H:15]([CH2:13][CH3:14])[CH2:16]4)[N:22]3[CH2:43][C:44]([F:47])([F:46])[F:45])=[C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)=[CH:37][N:38]=1
Reactant: C[C@H](O)C(=O)O
Reactant: CC[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)[C@H](C)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 27.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72.4 mg, 0.38 mmol) was added to an N,N-dimethylformamide solution (5 ml) of 5-{8-[(3R)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (124 mg, 0.25 mmol), triethylamine (0.087 ml, 0.63 mmol), L-lactic acid (27.2 mg, 0.30 mmol), and 1-hydroxybenzotriazole (42.6 mg, 0.28 mmol), the resulting mixture was stirred at room temperature for 17 hours followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72.4 mg, 0.38 mmol), and the resulting mixture was stirred at 40° C. for 8 hours. The resulting mixture was partitioned with ethyl acetate and water and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=90:10) to give the title compound (38.9 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[C@@H:18]4[CH2:19][C@@H:15]([CH2:16][CH2:17]4)[N:14]3[C:20](=[O:31])[C@@H:21]([NH:26][C:27](=[O:30])[O:28][CH3:29])[C@H:22]([O:24][CH3:25])[CH3:23])=[N:10][CH:9]=2)=[C:4]([F:32])[CH:3]=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([NH:65][C:66](=[O:69])[O:67][CH3:68])[C:36](=[O:64])[N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]1[NH:46][C:45]2[C:47]3[C:52]([CH:53]=[CH:54][C:44]=2[N:43]=1)=[CH:51][C:50](B1OC(C)(C)C(C)(C)O1)=[CH:49][CH:48]=3.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:68][O:67][C:66]([NH:65][C@@H:35]([CH:34]([CH3:70])[CH3:33])[C:36]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]1[NH:46][C:45]2[C:47]3[C:52]([CH:53]=[CH:54][C:44]=2[N:43]=1)=[CH:51][C:50]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]4[C@@H:18]5[CH2:19][C@@H:15]([CH2:16][CH2:17]5)[N:14]4[C:20](=[O:31])[C@@H:21]([NH:26][C:27](=[O:30])[O:28][CH3:29])[C@H:22]([O:24][CH3:25])[CH3:23])=[N:10][CH:9]=2)=[C:4]([F:32])[CH:3]=1)=[CH:49][CH:48]=3)=[O:64])=[O:69]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1C(c2ncc(-c3ccc(Br)cc3F)[nH]2)[C@H]2CC[C@@H]1C2)[C@@H](C)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc(C6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)c(F)c4)ccc3c2[nH]1)C(C)C
Yield: 47.8 %

Procedure:
Methyl (2S,3R)-1-((1R,4S)-3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate (162 mg, 0.318 mmol), methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (199 mg, 0.382 mmol), Pd(PPh3)4 (37 mg, 0.0318 mmol) and K2CO3 (2M in H2O, 0.4 mL, 0.8 mmol) were suspended in DME (3 mL). The reaction mixture was degassed with N2 for 11 min then heated to reflux for 2.5 h. Upon completion, the reaction mixture was diluted with MeOH, filtered over a thiol SPE column and concentrated. The crude residue was purified by silica column chromatography (0% to 50% MeOH/EtOAc) to afford the title compound (125 mg, 48%). (ESI) m/z 823 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([C@@H](Cl)C([O-])=O)[C:10]2=[O:19])=[O:8])=[CH:5][CH:4]=1.NC(N)=S.C([OH:28])C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:10](=[O:19])[CH:11]([OH:28])[CH2:12][CH2:13]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1ccc(C(=O)N2CC[C@H]([C@@H](Cl)C(=O)[O-])C2=O)cc1
Agent: NC(N)=S
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCC(O)C2=O)cc1
Reaction time: 8 h

Procedure:
1.54 g of (R,S)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinylchloroacetate are heated at 100° C. in 50 ml of pyridine for 10 minutes under nitrogen with 0.42 g of thiourea and 7 ml of ethanol. The solvent is removed by evaporation and the residue is partitioned between ethyl acetate and water. The organic phase is washed several times with water and the aqueous phases are extracted with ethyl acetate. The combined ethyl acetate phases are evaporated, the residue is boiled at reflux in diisopropyl ether and then the solution is decanted off from insoluble constituents. The clear, colourless diisopropyl ether phase is stirred in an ice-bath and then left to stand in an ice box overnight. The product which crystallises out is filtered off and there is obtained (R,S)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone of melting point 125°-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[N:22]=[CH:23][S:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4ncsc4c3)n2)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5ncsc5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.36 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzothiazol-6-yl-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(benzothiazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-4-tert-butyl-benzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][C:5]=1[OH:18])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][C:5]=1[OH:18]
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2)cc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A mixture of 4-nitro-3-hydroxybenzophenone (900 mg, 3.7 mmol) and tin (II) chloride (2.5 g, 11.1 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (685 mg, 87%). 1H NMR (CD3OD): δ7.65 (d, 2H), 7.55 (d,1H), 7.49 (t, 2H), 7.26 (s, 1H), 7.16 (dd, 1H), 6.68 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1[C:34]2[CH:35]=[CH:36][CH:37]=C[C:33]=2[N:32]=[N:31]1.NN1CCCCC1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([NH:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 86.4 %

Procedure:
2,4-bis-benzyloxy-5-isopropylbenzoic acid (F67-01: 188 mg, 0.5 mmol), dimethylformamide (2 mL) and 1-hydroxy-1,2,3-benzotriazole (72 mg, 0.55 mmol) were placed in a test tube and then 1-amino-piperidine (0.059 mL, 0.55 mmol) was added. A mixed solution of dimethylformamide (1 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and triethylamine (0.15 mL, 1.1 mmol) was slowly added to the reaction mixture at 0° C. while stirring. Further, the reaction mixture was allowed to come to room temperature and stirred for 24 hours. After completing the reaction, the reaction mixture was extracted with ethyl acetate, and the extract was washed 4 times with saturated sodium chloride, dried with sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol) followed by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (F67-02: 198 mg, 86.4%).