Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[C:10](O)=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:7][CH:6]=1)[CH3:2].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[C:10]([Cl:25])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:7][CH:6]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(-c2ccccc2C(F)(F)F)cc1O
Product: CCOC(=O)c1cnc(-c2ccccc2C(F)(F)F)cc1Cl

Procedure:
Heat a mixture of 4-Hydroxy-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester (9.0 g, 0.029 mol) in POCl3 (22 g) at 110° C. for 2 hours. Evaporate the POCl3, and add ice (100 g) followed by careful addition of saturated NaHCO3. Extract with EtOAc, dry (MgSO4), and evaporate to provide 4-chloro-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:31])([CH3:30])[CH2:10][C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:20](=[O:21])[O:19][CH2:18]2)=[O:13].N1C=CC=CC=1.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:38]([CH3:41])(=[O:40])=[O:39])=[C:3]([C:9]([CH3:31])([CH3:30])[CH2:10][C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:20](=[O:21])[O:19][CH2:18]3)=[O:13])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1NS(C)(=O)=O

Procedure:
17.7 mg of 5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide, 0.4 ml of pyridine and 0.078 ml of mesyl chloride are stirred for 17 hours at room temperature, mixed with ethyl acetate, and washed three times with 1N hydrochloric acid. The ethyl acetate solution is dried and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane (1:1), 11 mg of 5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide is obtained, flash point 218° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[H-].[Na+]>CN(C=O)C.O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH2:18])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Nc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1Oc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Temperature: 50 °C

Procedure:
To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.52 g, 2.0 mmol) and 2-aminophenol (0.26 g, 2.4 mmol, Aldrich) in DMF (10 mL) was added sodium hydride (0.09 g, 2.2 mmol, 60% dispersion in mineral oil, Aldrich). The mixture was heated at 50° C. for 2 h, allowed to cool to room temperature and diluted with H2O. The resulting solid was filtered, washed with H2O and dried in vacuum at room temperature for 20 h to afford the title compound as a white powder. Mp: 188° C., MS (ESI, pos. ion) m/z: 332 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23]C1C=CC(C2(C(O)=O)CCC2)=CC=1>>[F:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCC1
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Product: Oc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2

Procedure:
The compound was prepared analogously to 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (cf. example 82) starting from 1-(4-fluorophenyl)cyclobutanecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[C:25]([CH3:33])([CH3:32])[CH2:24][CH2:23][N:22]3[CH:21]=1)=O>>[CH3:32][C:25]1([CH3:33])[C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:21][N:22]3[CH2:23][CH2:24]1)[CH:29]=[CH:28][CH:27]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)C(C)(C)CC2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5cc(F)ccc45)C(=O)NC3=O)c3cccc1c32

Procedure:
Beginning with (6-fluoroindol-3-yl)acetamide and (6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([C:28]1[CH:36]=[C:35]([CH2:37]Br)[CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[C@H:5]([CH2:37][C:35]1[CH:36]=[CH:28][C:29]([C:30]([O:32][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:31])=[CH:33][CH:34]=1)[N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: O=C(O)c1ccc(CBr)cc1Cc1ccccc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(C(=O)OCc2ccccc2)cc1)N=C(c1ccccc1)c1ccccc1
Yield: 212.4 %

Procedure:
A mixture of N-(diphenylmethylene)glycine ethyl ester (6.6 g, 24.9 mmol), benzyl 4-(bromomethyl)benzoic acid (7.61 g, 24.9 mmol) and potassium carbonate (50 mmol, 6.9 g) in acetonitrile (300 ml) was refluxed overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as an oil (13.0 g) δH (CDCl3) 7.90 (2 H, d, J 8.3 Hz), 7.58 (2 H, d, J 7.3 Hz), 7.50-7.25 (11 H, m), 7.14 (2 H, d, J 8.1 Hz), 6.65 (2 H, d, J 6.8 Hz), 5.33 (2 H, m), 4.30-4.15 (3 H, br m), 3.32 (2 H, v br s) and 1.26 (3 H, t, J 7.1 Hz); m/z (ESI, 60 V) 492 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35](=[O:48])[CH:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:48])[CH:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCI)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of triphenylphosphine (734 mg, 2.80 mmol) and imidazole (191 mg, 2.80 mmol) in CH2Cl2 (10 ml) at rt was added iodine (711 mg, 2.80 mmol) portionwise over 5 min. The mixture first turned yellow, then brown and developed precipitate. The mixture was stirred at rt until no pieces of iodine were visible (approx. 5 min.). A solution of alcohol from step (38b) (721 mg, 2.33 mmol) in CH2Cl2 (5 ml) was added and the resulting mixture was stirred at rt for 1 h. The reaction was filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0-25% EtOAc/Hexane) gave 2-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (430 mg, 44%) as a slightly yellow oil: 1H NMR (500 MHz, Methanol-D) δ 7.24-7.42 (m, 5 H), 5.07-5.25 (m, 2 H), 4.16-4.31 (m, 1 H), 3.12-3.29 (m, 2 H), 2.01-2.35 (m, 2 H), 1.42 (s, 9 H). LC-MS (Method A, retention time: 1.71 min), MS m/z 420 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[C:10]=1[CH3:11].CS[C:16]1[N:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:19][N:20]=1>>[CH3:24][O:23][C:21]([N:17]1[CH2:18][CH2:19][NH:20][C:16]1=[N:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[NH:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH3:11])=[O:22]
Reactant: Cc1c(N)cc(C#N)c2nc[nH]c12
Reactant: COC(=O)N1CCN=C1SC
Product: COC(=O)N1CCNC1=Nc1cc(C#N)c2[nH]cnc2c1C

Procedure:
There are many suitable methods for coupling intermediate (10) with side chain 4,5-Dihydro-2-(methylthio)-1H-imidazole-1-carboxylic Acid, Methyl Ester (29). Referring to General Scheme (4), intermediate (10) is coupled to side chain (29) to yield intermediate 2-(7-Cyano-4-methyl-1H-benzimidazol-5-yl-imino)-imidazolidine-1-carboxylic Acid Methyl Ester (30), and thereafter deprotected to yield product 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile (31a) as the preferred anhydrous, monoacetate salt (which can be further purified by recrystallization to yield final product (31b)). See Example 5. The assay described in Example 3 may be used to analyze products (31a) and (31b) for the level of 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile that is present. In one embodiment, the preferred anhydrous monoacetate salt of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile (31a) and (31b) that is produced is substantially free of 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile. In one embodiment, the preferred anhydrous monoacetate salt of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile (31a) and (31b) that is produced contains less than 70 ppb (parts per billion), preferably less than 15 ppb, more preferably less than 5 ppb, of 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile. Other solvent systems that may be used to recrystallize product (31a) to yield final product (31b) include: ethanol/water, acetone/water, acetonitrile/water, tetrahydrofuran/water, methanol, N,N-dimethylacetamide, and acetonitrile. Although in General Scheme 4 intermediate (30) is carried forward without isolation, it may be isolated as shown in Example 16. Another method to attach the side chain includes Example 17. Still another suitable method is described in U.S. Pat. No. 6,066,740.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]2=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:47][C:48]3[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:65])[F:66])[CH:58]=4)[CH:51]=[CH:52][C:53]=3[CH3:54])=[O:13])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1cc2nc(Cl)cnc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A solution of 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (219 mg, 1.019 mmol), HATU (465 mg, 1.223 mmol) and DIPEA (0.337 mL, 2.039 mmol) in DMF (6 mL) was stirred for 15 min at rt. N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (300 mg, 1.019 mmol) was added and stirred overnight at rt and overnight at 60° C. The reaction mixture was poured out in 3% citric acid solution and the resulting precipitate was collected and washed with water to give compound 2-chloro-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 68 (389 mg, 78%). (m/z)=491 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:37])[NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)[CH2:25][CH2:24]4)=[C:17]3[N:16]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[O:37])[CH2:27][CH2:28]4)=[C:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)c1
Reaction time: 1 h
Yield: 109 %

Procedure:
To (3-{6-Bromo-7-[4-(thiazol-2-ylcarbamoylmethyl)-piperazin-1-yl]-3H-imidazo[4,5-b]pyridin-2-yl}-benzyl)-carbamic acid tert-butyl ester (0.027 g, 0.04 mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (0.5 mL) at 0° C. trifluoroacetic acid (0.25 mL) was added and the reaction mixture was stirred for 1 h. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was run trough a 2 g SCX cartridge and eluted with 0.1M NH3 in methanol to give the title compound as a pale yellow solid (0.023 g, 100%);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[CH:18]=1)=[O:8])[CH3:2].[Cl:20]N1C(=O)CCC1=O.O1CCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[C:18]=1[Cl:20])=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Yield: 57.2 %

Procedure:
0.86 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester was suspended in 30 ml of ethyl acetate; 1.2 g of N-chlorosuccinimide was added, followed by thermal refluxing for 20 hours. After cooling, 30 ml of tetrahydrofuran was added; the mixture was washed with an aqueous solution of sodium thiosulfate and saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; ethyl ether was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 0.552 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]1[CH:21]=[CH:20][C:13]2[N:14]([CH3:19])[C:15]([CH2:17][NH2:18])=[N:16][C:12]=2[CH:11]=1)=[O:9].FC(F)(F)C([O-])=O.C(N(C(C)C)C(C)C)C.Cl[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][N:47]=1.Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]1[CH:21]=[CH:20][C:13]2[N:14]([CH3:19])[C:15]([CH2:17][NH:18][C:46]3[N:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Temperature: 100 °C

Procedure:
1.5 g (3.25 mmol) of 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-trifluoracetate were stirred into 10 ml of N-ethyl-diisopropylamine and heated to 100° C. for 15 minutes. After the addition of 720 mg (5.25 mmol) of 2-chloro-5-cyano-pyridine the reaction mixture was heated to 125° C. for 2 hours. After cooling to ambient temperature and stirring with about 20 ml of water, the pH was adjusted to 4 by the addition of 1N hydrochloric acid and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with saline solution and dried over sodium sulphate. After evaporation of the solvent the crude product was chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated down.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(c1ccc(O)cc1)c1nc2ccc(Br)cc2o1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3ccc(Br)cc3o2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
A mixture of 4-[N-methyl-N-(6-bromo-2-benzoxazolyl)amino]phenol (0.6, 0.002 mole), ethyl 2-bromopropionate (0.4 g, 0.002 mole), anhydrous potassium carbonate (0.3 g, 0.002 mole) and methyl ethyl ketone (6 ml) was heated under reflux, with stirring, for a period of 3 hours. Thin layer chromatography indicated that the reaction had not gone to completion and therefore further anhydrous potassium carbonate (0.15 g) and methyl ethyl ketone was added and the mixture was heated under reflux for a further period of 3 hours. The solvent was removed by distillation under reduced pressure, water (50 ml) was added to the residue and the aqueous mixture was extracted with diethyl ether (3×30 ml). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated to give a dark red oil. The oil was heated at a temperature of 100° C. at a pressure of 0.1 mm Hg for a period of 2 hours to remove residual ethyl 2-bromopropionate and the residue was recrystallised from hexane/cyclohexane to give the title compound as a white solid (0.45 g), mp 91°-92° C.
Reaction SMILES: [CH3:1][C:2]1C=C[C:5]2[N:6]([C@@H:9]3[C@@H:16]4[C@@H:12]([CH2:13][N:14]([C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=5)[CH2:15]4)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:29][C:30]1C=CC2N=CN([C@@H]3[C@@H]4[C@@H](CN(C5C=CC=C(C(F)(F)F)N=5)C4)CC3)C=2[CH:56]=1>>[C:3]1([C:4]2[N:8]=[CH:7][N:6]([C@@H:9]3[C@@H:16]4[C@@H:12]([CH2:13][N:14]([C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]=5)[CH2:15]4)[CH2:11][CH2:10]3)[CH:5]=2)[CH:2]=[CH:1][CH:56]=[CH:30][CH:29]=1
Reactant: Cc1ccc2ncn([C@H]3CC[C@@H]4CN(c5cccc(C(F)(F)F)n5)C[C@@H]43)c2c1
Reactant: Cc1ccc2c(c1)ncn2[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: FC(F)(F)c1cccc(N2C[C@H]3CC[C@H](n4cnc(-c5ccccc5)c4)[C@H]3C2)n1

Procedure:
5-methyl-1-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-1H-benzimidazole and 6-methyl-1-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-1H-benzimidazole;
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9](F)[C:8]([F:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]>CO>[Cl:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[C:8]([F:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To sodium methoxide (100 mL of a 0.5 M solution in methanol, 50.1 mmol) cooled to 0° C. was added a solution of 1-chloro-4,5-difluoro-2-nitro-benzene (9.7 g, 50.1 mmol) in methanol (10 mL) dropwise over 15 min. The solution was warmed to room temperature and stirred for 2 h, then poured slowly over ice. The yellow precipitate was collected by filtration and washed with cold water. The crystals were air dried to give 8.2 g (79%) of 1-chloro-4-fluoro-5-methoxy-2-nitro-benzene: Crude 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J=10.5 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 3.98 (s, 3H). The crude material was pure enough to carry on to the next step.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.N#N.[H][H]>CO.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1cnc(C2=CCOCC2)cn1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: Nc1cnc(C2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 5-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-amine (2.7 g, 15.24 mmol) and Pd—C (10%, Degussa type) (1.6 g, 1.5 mmol) in MeOH (50 mL) was degassed by N2 stream for 15 min. After equipped with hydrogen gas balloon, the reaction mixture was stirred for 15 h at room temperature. The crude product was filtered off through celite pad and washed with EtOAc. The volatile material was concentrated in vacuo yielding 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine and was used for the next step. LCMS (m/z): 180.3 (MH+), 0.28 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14])=[O:22]
Reactant: COc1cc(N)c2nccc(C)c2c1
Reactant: O=C(Cl)CCCCCBr
Product: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1

Procedure:
6-Methoxy-4-methyl-8-quinolinamine was converted to the title amide by reaction with 6-bromohexanoyl chloride in the usual manner.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: O=C(N1CCCCC1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
Added 0.590 g of 4-nitrophenyl 4-(4-nitrophenyl)piperazine-1-carboxylate to 5.0 mL piperidine and stirred at room temperature until complete. HPLC indicated that reaction was complete after 18 hrs by absence of starting material. Material was added to 15 mL ice water and precipitate formed which was filtered to obtain (4-(4-nitrophenyl)piperazin-1-yl)(piperidin-1-yl)methanone as a yellow powder. Product was allowed to dry under vacuum for 24 hrs (0.426 g, 84.4% yield).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([O:12][C:13]([C@@H:15]1[CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17][C@H:16]1[C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])=[O:14])[CH3:11]>C1COCC1>[CH2:10]([O:12][C:13]([C@@H:15]1[CH2:19][C@@H:18]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:17][C@H:16]1[C:25]([N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)=[O:26])=[O:14])[CH3:11]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)N1CCOCC1

Procedure:
To a solution of the thiophenol (0.41 mmol) in THF (4 ml) was added NaH (55% in oil, 0.41 mmol) at 22° C. and stirring was continued until gas evolution ceased. To the mixture was added a solution of (1R,2R,4R)-4-methanesulfonyloxy-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester (0.28 mmol) in THF (4 ml) and stirring was continued at 50° C. until completion of the reaction. The mixture was partitioned between ethyl acetate and water, the organic layer was dried, evaporated and the residue chromatographed on silica using mixtures of cyclohexane and ethyl acetate to give the title compound as pale yellow oil. MS: 364.5 (M+H)+.