Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:34])[CH2:18][O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=1[C:22](=[O:33])[CH:23]=[C:24]([C:30]([OH:32])=[O:31])[O:25]3)[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[C:35]([NH:54][C@H:55]([C:59]([O:61][CH2:62][CH:63]([CH2:70][O:71][C:72](=[O:90])[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[CH2:64][CH2:65][CH2:66][C:67](O)=[O:68])=[O:60])[CH:56]([CH3:58])[CH3:57])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:35]([NH:54][C@H:55]([C:59]([O:61][CH2:62][CH:63]([CH2:70][O:71][C:72](=[O:90])[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[CH2:64][CH2:65][CH2:66][C:67]([O:34][CH:17]([CH2:16][O:15][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:14])[CH:13]=[C:4]([C:1]([OH:3])=[O:2])[O:5]2)[CH2:18][O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22](=[O:33])[CH:23]=[C:24]([C:30]([OH:32])=[O:31])[O:25]2)=[O:68])=[O:60])[CH:56]([CH3:58])[CH3:57])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)O)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Reactant: O=C(O)c1cc(=O)c2c(OCC(O)COc3cccc4oc(C(=O)O)cc(=O)c34)cccc2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)OC(COc1cccc2oc(C(=O)O)cc(=O)c12)COc1cccc2oc(C(=O)O)cc(=O)c12)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Reaction time: 72 h

Procedure:
To a solution of the dibenzyl ester of 1,3-bis-(2-carboxychromon-5-yloxy)propan-2-ol (270 mg, 0.42 mmole), 5-(N-Trityl-L-valyloxymethyl)-6-stearoyloxyhexanoic acid (323 mg, 0.42 mmol) and dimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane was added DCC (92 mg, 0.45 mmol). After 3 days, the reaction mixture was filtered through Celite and the filtrate was washed with sodium hydrogen carbonate aqueous solution and dried. The product dibenzyl ester of 2-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane was isolated from silica gel column chromatography. 250 mg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[N:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:22].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[N:18]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cnc(N2CCNCC2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-chloro-3,5-dimethylpyrazine (2.8 g), 1-Boc-piperazine (3.7 g), palladium (II) acetate (225 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (953 mg) and sodium tert-butoxide (2.7 g) was added toluene (40 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 3′,5′-dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (5 g). 3′,5′-Dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (5 g) was dissolved in chloroform (15 mL), 4N hydrogen chloride/ethyl acetate (15 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (3.3 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[O-:39][CH2:40][CH3:41].[Na+].O1CCCC1.CS(C)(=O)=O>O1CCCC1>[CH2:40]([O:39][C:14]1[N:13]=[C:12]([NH:11][C@H:7]2[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]2)[C:17]([C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:16][N:15]=1)[CH3:41]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CC[O-]
Agent: CS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a tetrahydrofuran solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, sodium ethoxide/tetrahydrofuran was used to displace the methylsulfone similar to the example above and the de-protection step was similar to step 5, Example 76 to give [2-ethoxy-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 418.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1COCC1>[N+:17]([C:16]1[C:11]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: OC1CCOCC1
Reactant: O=[N+]([O-])c1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccnc1OC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a stirred solution of tetrahydro-2H-pyran-4-ol (2.5 g, 24.5 mmol) in anhydrous THF (20 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 0.938 g, 24.5 mmol) and the mixture stirred at 0° C. for 0.5 h. A solution of 2-fluoro-3-nitro-pyridine (3.3 g, 23.2 mmol) in anhydrous THF (5 mL) was added drop wise with stirring and the solution allowed to warm to ambient temperature over 5 hours. The reaction was cooled in an ice-bath and water (50 mL) added. The mixture was extracted with EtOAc (2×100 mL) and the combined organic layers washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified flash column chromatography (20% iso-hexane/DCM DCM) to yield the title compound as pale yellow oil (2.67 g, 48% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=N)[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.C(O)(=[O:34])C.Cl.C(=O)(O)[O-].[Na+]>O>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:34])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2
Reactant: CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Temperature: 25 °C

Procedure:
15.5 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl chroman-2-yl-methoxy) benzyl]-2-iminothiazolidine-4-one, prepared by the process as described in Example-1, was added to a mixture of 225 ml of acetic acid, 75 ml of conc. hydrochloric acid and 40 ml of water and the mixture was refluxed for 12 hrs. The reaction mixture was cooled to room temperature and 66.2 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the crude product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution & water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off. The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 12.5 g of the required 5-{4-(6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl-methoxy) benzyl) thiazolidine-2,4-dione (Troglitazone) with a HPLC purity of ~67-70%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN(C2CCNCC2)C1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 4-pyrrolidin-1-yl-piperidine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C35H42N6O2Cl2 [(M+H)+] 649.2819, observed 649.2822.
Reaction SMILES: [Cl:1]C1SC=C(C2C(=O)NC(=O)NC2=O)C=1.Cl[C:17]1[S:21][CH:20]=[C:19]([CH:22]2[O:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])[CH:18]=1>>[Cl:1][C:20]1[S:21][CH:17]=[CH:18][C:19]=1[CH:22]1[O:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: O=C1NC(=O)C(c2csc(Cl)c2)C(=O)N1
Reactant: O=C1NC(=O)C(c2csc(Cl)c2)O1
Product: O=C1NC(=O)C(c2ccsc2Cl)O1

Procedure:
The same procedure is employed to convert 5-(5-chloro-3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione to 5-(5-chloro-3-thienyl)oxazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][C:9](=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:18].[Na+].Cl>CO>[NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:18])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Nc1nc2c(s1)CC(=O)CC2
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Nc1nc2c(s1)CC(N)CC2
Yield: 70.3 %

Procedure:
A solution of 2-amino-6-oxo-4,5,6,7-tetrahydro-1,3-benzothiazole (2.0 g, 12 mmol), ammonium acetate (9.2 g, 120 mmol) and sodium cyanoborohydride (0.53 g, 8.4 mmol) in 40 mL of methanol was stirred under nitrogen at ambient temperature for 48 hours. Concentrated HCl was added and methanol was removed in vacuo. The residue was mixed with water and solution was made alkaline with NaOH. White precipitate was removed by filtration, washed with water and dried to give 1.0 g of the title compound. The structure of the product was confirmed by NMR.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[C:4]([CH3:21])[CH:3]=1.C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.C(C1C=C(NC(=O)C2C=CC(N3CCNCC3)=C(F)C=2)C=CC=1)(C)(C)C>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:3][C:4]=2[CH3:21])[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(Br)ccc1C(=O)Nc1cccc(C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Product: Cc1cc(N2CCNCC2)ccc1C(=O)Nc1cccc(C(C)(C)C)c1

Procedure:
N-(3-tert-Butyl-phenyl)-2-methyl-4-piperazin-1-yl-benzamide was synthesized from 4-bromo-N-(3-tert-butyl-phenyl)-2-methyl-benzamide and piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide above. LCMS calcd for C22H29N3O (m/e) 351, obsd 352 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[C:32]1(B(O)O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:14])=[O:13])(=[O:22])=[O:23]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc4ccccc34)c2c1
Yield: 58 %

Procedure:
2-Methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 298 mg of 1-naphthaleneboronic acid, 20 ml of dimethylformamide, 1.9 ml of a saturated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 240 mg of 2-methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 186° C. (analysis C24H19N3O4S2 % calculated C, 60.36; H, 4.01; N, 8.80; O, 13.40; S, 13.43. % found C, 59.78; H, 4.05; N, 8.76; S, 13.34).
Reaction SMILES: C[C@@H](NC)[C@@H](O)C1C=CC=CC=1.[Cl:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([NH:24][CH:25]([C:34]3[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=3[C:36](O)=[O:37])[CH2:26][C:27](=[O:33])[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[N:21]2)=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([N:24]3[CH:25]([CH2:26][C:27](=[O:33])[CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:37])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Agent: CN[C@H](C)[C@@H](O)c1ccccc1
Solvent: ClCCl
Product: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
118.3 g of the salt of (+)-ephedrine and (±)-2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid and 1700 cm3 of methylene chloride are introduced into a 2.5 liter reactor. The organic solution is washed, at 20° C., with 400 cm3 of a 0.5N aqueous hydrochloric acid solution and then with 400 cm3 of distilled water. The organic phase is dehydrated by azeotropic distillation at 20° C. under reduced pressure (250 mm of mercury; 33.3 kPa). The volume of the organic phase is adjusted to 1700 cm3 by addition of dry methylene chloride, 95.2 g of imidazole are then added and then, over 10 minutes, 25 cm3 of thionyl chloride. The suspension is heated at 40° C. for 30 minutes, then cooled to 20° C. and washed with 2 times 700 cm3 of distilled water. The methylene chloride is removed by distillation at atmospheric pressure while adding, to keep the volume constant, 2500 cm3 of absolute ethanol. When the temperature of the vapour reaches 78° C., the distillation is halted and 4 g of decolorizing charcoal in suspension in 20 cm3 of absolute ethanol are then added. The mixture is left for 30 minutes at 78° C. and then filtered while hot. The decolorizing charcoal is rinsed with 200 cm3 of ethanol at 77° C. The wash and the filtrate are combined and then cooled, at a rate of 20° C./hour, to a temperature of 10° C. The suspension is filtered. The precipitate is washed with 3 times 140 cm3 of absolute ethanol at 10° C. and then dried at 60° C. for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). The slightly yellow product obtained (68.9 g) is recrystallized from 1400 cm3 of ethanol at reflux. After cooling to 10° C., the suspension is filtered. The precipitate is washed with 3 times 100 cm3 of absolute ethanol at 10° C. and then dried at 60° C. for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 65.1 g of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]12[CH2:26][CH:23]([CH:24]=[CH:25]1)[CH2:22][CH:21]2[CH2:27]O.C(Cl)(Cl)(Cl)[Cl:30]>>[Cl:30][CH2:27][CH:21]1[CH2:22][CH:23]2[CH2:26][CH:20]1[CH:25]=[CH:24]2
Reactant: OCC1CC2C=CC1C2
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCC1CC2C=CC1C2

Procedure:
A mixture of triphenylphosphine (20.98 g, 0.08 mol) and bicyclo[2.2.1]hept-5-ene-2-methanol (5.0 g, 0.0403 mol) in dry carbon tetrachloride (31.5 ml) was stirred and heated at 60° for 6 h. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to afford a semi-crystalline mass, which was triturated with n-pentane (100 ml). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a yellow oil. Distillation of the oil afforded 5-chloromethylbicyclo[2.2.1]hept-2-ene as a colourless oil, b.p. 70°-72°/24 mm Hg.
Reaction SMILES: [CH:1]([NH:3][C:4]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)([C:10](OCC)=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2].[H][H]>C(O)(=O)C.[Pt]=O>[O:11]=[C:10]1[C:4]([NH:3][CH:1]=[O:2])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][C:16]2=[CH:17][CH:18]=[CH:19][C:20]3=[C:25]2[N:24]1[CH2:23][CH2:22][CH2:21]3
Reactant: CCOC(=O)C(Cc1cccc2cccnc12)(NC=O)C(=O)OCC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC=O)Cc2cccc3c2N(CCC3)C1=O
Yield: 96.6 %

Procedure:
A mixture of diethyl (formylamino)(8-quinolinylmethyl)malonate (9.2 g, 26.7 mmol) and platinum oxide (0.7 g) in glacial acetic acid (150 mL) was hydrogenated (50 lb initial pressure) for 15 minutes (hydrogen uptake ca. 2 equiv). The mixture was filtered through celite and the solvent removed under reduced pressure. The product was partitioned between ethyl acetate and sodium hydroxide solution. The ethyl acetate phase was washed with water, the ethyl acetate was evaporated, and the product was crystallized from ether to give 7.8 g (97%) of ethyl 2,3,6,7-tetrahydro-3-oxo-2-(formylamino)- 1H,5H-benzo(ij)quinolizine-2-carboxylate, mp 103°-106° C. Anal. Calc'd for C16H18N2O4 : C, 63.56; H, 6.00; N, 9.27. Found: C, 63.51; H, 6.09; N, 9.18.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1)(=[O:3])[CH3:2]
Reactant: Cn1ccc(N)n1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccn(C)n2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-amino-1-methylpyrazol (40 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature during three hours and the final product was collected by filtration and washed with diethylether to yield the title compound (56 mg, 59.6% yield).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:18]([NH2:20])=O)[C:12](=[CH:16][CH:17]=1)[C:13]([NH2:15])=O)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:18]#[N:20])[C:12](=[CH:16][CH:17]=1)[C:13]#[N:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(C(N)=O)c(C(N)=O)c1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1ccc(C#N)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of 7.0 g (25.1 mmol) 4-ethoxalylaminophthalamide in 75 ml dry pyridine was gradually added 4.1 ml (44.8 mmol) phosphorus oxychloride. Stirring was continued at 25° C. for 30 min. The reaction mixture was poured into 300 ml ice-cooled 4N hydrochloric acid to give 4.7 g (77%) of 4-ethoxalylaminopthalonitrile. M.p. 193.7° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].C(Cl)(Cl)Cl>C(N(CC)CC)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(I)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to dimethylamine (1.8 g) in triethylamine (40 ml) at 0°. The suspension was stirred at 0° for 1 h, treated with chloroform (200 ml), washed with aqueous sodium bicarbonate (1 M; 100 ml), dried and evaporated to give the title compound (9.7 g) m.p. 103°-106°.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])C.O[Li].O>O>[C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THlF/water solution (75 mL) was added a solution LiOH.H2O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50° C. overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:14][N:13]([C:15]([C:17]3[S:21][C:20]4[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:19]=4[CH:18]=3)=[O:16])[CH2:12]2)[CH2:7][CH2:6]1)=O>CO>[N:8]1([CH:11]2[CH2:14][N:13]([C:15]([C:17]3[S:21][C:20]4[CH:22]=[C:23]([C:26]([F:28])([F:27])[F:29])[CH:24]=[CH:25][C:19]=4[CH:18]=3)=[O:16])[CH2:12]2)[CH2:9][CH2:10][NH:5][CH2:6][CH2:7]1
Reactant: O=C(c1cc2ccc(C(F)(F)F)cc2s1)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Solvent: CO
Product: O=C(c1cc2ccc(C(F)(F)F)cc2s1)N1CC(N2CCNCC2)C1

Procedure:
A solution of 2,2,2-trifluoro-1-(4-(1-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)azetidin-3-yl)piperazin-1-yl)ethanone (1.12 mmol, 520 mg) in 20 mL of methanol and TEA (2 mL) was stirred at room temperature for 3 days. The resulting mixture was concentrated to yield (3-(piperazin-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]thiophen-2-yl)methanone, which was used in the next step without purification.