Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:7](=[O:16])[NH:8]2)=[N+]=[N-].[OH-].[NH4+].[H][H]>C1COCC1.[Pt]>[NH2:1][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:7](=[O:16])[NH:8]2
Reactant: [H][H]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N=[N+]=[N-])c21
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21

Procedure:
(Z)-4-Azido-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (2.08 g, 6.37 mmol) (from Example 14) was dissolved in THF (160 mL) at r.t. Ammonium hydroxide was added (2 mL), followed by a catalytic amount of poisoned platinum on carbon (300 mg). The reaction mixture was hydrogenated in a Parr bomb under 50 psi of hydrogen for 12 h. The mixture was filtered through a cake of Celite®, the cake was washed twice with THF, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on Silica Gel (230-400 mesh, eluted with 75% ethyl acetate in hexanes) to yield (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 1.44 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([N:13]=[C:14]=[S:15])[CH:12]=1>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([NH:13][C:14](=[S:15])[NH:1][CH2:2][C:3]([NH2:5])=[O:4])[CH:12]=1
Reactant: NCC(N)=O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
Glycinamide (10.08 g) and 5-chloro-2-methylphenyl-isothiocyanate (23 g) were heated at reflux in chloroform (300 mL) for 30 minutes. The mixture was then stirred at ambient temperature for 3 hours. The precipitated solid was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (28.5 g), m.p. 162°-1640° C. Mass spectrum (EI, M.+) m/z 257/259. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.46 (s, 1 H), 7.83 (s, 1 H), 7.51 (d, 2 H), 7.24 (d, 1 H), 7.24 (d, 1 H), 7.18 (d, 1 H), 7.15 (m, 2 H), 4.06 (d, 2 H), and 2.16 ppm (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([CH3:36])[C:31]=1[S:37](Cl)(=[O:39])=[O:38].Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:37]([C:31]2[C:32]([CH3:36])=[N:33][N:34]([CH3:35])[C:30]=2[Cl:29])(=[O:38])=[O:39])=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Nc1ccc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)nc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A solution of 2-(5-amino-pyridin-2-yl)-malonic acid dibenzyl ester in pyridine cooled to 0° C. was treated with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride. The reaction mixture was allowed to slowly warm to 25° C. and was stirred at 25° C. for 24 h. At this time, the reaction mixture was cooled to 0° C. and acidified to pH=1 with 3.0M aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate. The organics were washed with a 1.0M aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 65/35 ethyl acetate/hexanes) afforded 2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-malonic acid dibenzyl ester (55%) as a colorless solid; LRMS for C27H25ClN4O6S (M+H)+ at m/z=569/571.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([F:27])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([C:23]([F:24])([F:25])[F:26])=[C:21]([F:27])[CH:20]=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.15 g (0.09 mol) of magnesium filings are introduced into 4.8 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 12.8 g (0.075 mol) of diethyl malonate in 9 ml of ethanol and 35 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50 and 60° C. Stirring is then continued for one hour at 60° C. A solution of 20.0 g (0.082 mol) of 2,4-difluoro-3-trifluoromethylbenzoyl chloride in 9 ml of toluene is added dropwise at -10° to -5° C., and stirring is continued for one hour at 0° C. and subsequently while the mixture comes to room temperature. The batch is poured into 35 ml of ice-water, treated with 5.7 ml of concentrated sulphuric acid, and the mixture is extracted using toluene. The toluene phase is washed using saturated sodium chloride solution, and the solvent is removed in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].C([Li])CCC.[CH:18](=[O:22])[CH2:19][CH2:20][CH3:21].C(O)(=O)C>C1COCC1.O>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[CH:18]([OH:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC=O
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(F)(F)F)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (0.30 mL, 2.1 mmol) in THF (6 mL) was added dropwise 1.5M butyllithium in THF (1.65 mL) at −78° C. The mixture was stirred at −78° C. for 15 minutes, to which was added a solution of butyraldehyde (0.18 mL, 2.5 mmol) in THF (2 ml) at −78° C. After stirring at −78° C. for 30 minutes, the mixture was treated with acetic acid (1 mL)/THF (2 mL), and then followed by water at room temperature. The organic layer was separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give 1-[2-fluoro-4-(trifluoromethyl)-phenyl]butanol. To a suspension of the product and powdered Molecular sieves 3A (750 mg) in dichloromethane was added pyridinium chlorochromate (887 mg, 4.12 mmol). The mixture was stirred for 16 hours at room temperature, to which was added ether (20 mL) and silica gel (Wakogel C-300HG, 2 g). The mixture was stirred for 10 minutes at room temperature, and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1), to give the titled compound as a white crystal (323 mg, yield 67%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[N:20][C:9]=3[S:8][CH2:7][C:6]2=1.Cl.N1C=CC=CC=1>>[CH3:16][N:12]1[C:11]2[C:10]3[CH:17]=[CH:18][CH:19]=[N:20][C:9]=3[S:8][CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([OH:2])[CH:4]=2
Reactant: COc1ccc2c(c1)c1c(n2C)-c2cccnc2SC1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2c(c3cc(O)ccc31)CSc1ncccc1-2
Temperature: 180 °C

Procedure:
A mixture of 8-methoxy-11-methyl-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene, (100 mg, 0.355 mmoL) and pyridine HCl salt (410 mg, 3.55 mmoL) was sealed in a tube and heated to 180° C. for 2 hours. The reaction mixture was cooled and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with saturated NaHCO3, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc 1:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: Cl.O.[NH2:3]N.Cl.[CH2:6]([O:8][C:9](=[O:22])[C:10](=[CH:18][N:19](C)C)[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:7]>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[NH:3][N:19]=[CH:18][C:10]=1[C:9]([O:8][CH2:6][CH3:7])=[O:22])=[O:13])[CH3:16]
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c1C(=O)OCC
Temperature: 60 °C
Yield: 0 %

Procedure:
Under an atmosphere of argon, hydrazine monohydrate hydrochloride (1.91 g, 28 mmol) and HCl (36.5% in water, 2.8 ml) were added to a solution of 2-dimethylaminomethylene-3-oxo-succinic acid diethyl ester (6.8 g, 28 mmol) in ethanol (100 ml). The mixture was heated to 60° C. (3 h). The solvent was evaporated, and the residue was taken up in dichloromethane and washed (water). The organic layer was dried (Na2SO4), the solvent was evaporated and the title compound (1.81 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=383.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccc(Cl)cc2)CC1
Reactant: Fc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(Cl)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-chloro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2B) (0.10 g, 0.35 mmol), 2-chloro-5-fluoro-pyrimidine (0.047 g, 0.35 mmol) and triethylamine (0.099 mL, 0.71 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-chloro-benzyl ester. M.S. (M+1): 379.26
Reaction SMILES: COC1C=[CH:5][C:6]([CH2:11][C:12]2[N:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[C:15](OC)[C:16](OC)=[CH:17]3)=CC=1OC.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:36][C:37]2[N:46]=[CH:45][CH:44]=[C:43]3[C:38]=2[CH:39]=[C:40]([O:49][CH3:50])[C:41]([O:47][CH3:48])=[CH:42]3)=[CH:32][C:33]=1[O:34][CH3:35].Cl.C([Br:61])C(C1C=CC=CC=1)=O>CC(C)=O>[CH:11]1[CH:6]=[CH:5][N:21]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=12.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:36][C:37]2[N:46]=[CH:45][CH:44]=[C:43]3[C:38]=2[CH:39]=[C:40]([O:49][CH3:50])[C:41]([O:47][CH3:48])=[CH:42]3)=[CH:32][C:33]=1[O:34][CH3:35].[BrH:61]
Reactant: O=C(CBr)c1ccccc1
Agent: COc1ccc(Cc2nccc3cc(OC)c(OC)cc23)cc1OC
Agent: Cl
Solvent: CC(C)=O
Product: Br
Product: c1ccc2c(c1)ccn1cccc21
Yield: 97 %

Procedure:
A series of novel pyrrolo[2,1-a]isoquinoline dyes was prepared from readily available starting materials via a simple synthetic pathway. One such starting material is papaverine, a naturally occurring alkaloid that is relatively inexpensive and commercially available as its hydrochloride salt. Papaverine hydrochloride was converted to its free base in 97% yield. The free base was subsequently alkylated with phenacyl bromide in refluxing acetone to give 1 in 56% yield (Scheme 1). Refluxing the mixture for one hour produced good results; additional heating resulted in substantial decomposition of 1 to papaverine hydrobromide. Attempts to isolate 1 using benzene as solvent were unsuccessful. Sodium bicarbonate in water was mixed with 1 to give the cyclized product 2 in 82% yield. ##STR15##
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICc1ccccc1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: c1ccc(CN2CCN3c4c(cccc42)[C@@H]2CNCC[C@@H]23)cc1

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using benzyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as a viscous liquid. 1H NMR(CDCl3, 300 MHz) δ 1.60-2.0 (m, 2H), 2.55-2.95(m, 4H), 2.95-3.15 (m, 2H), 3.20-3.45 (m, 3H), 4,40 (q, J=16.1 Hz, 2H), 6.41 (d, J=7.1 Hz, 1H), 6.51 (d, J=7.1 Hz, 1H), 6.62 (t, J=7.1 Hz, 1H), 7.20-7.40 (m, 5H) ppm. MS (CI): 306 (M+H+).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[CH2:52][C:53]([O:55][CH3:56])=[O:54].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46][CH2:52][C:53]([O:55][CH3:56])=[O:54])=[O:45])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:50])[CH:8]=1
Reactant: COC(=O)CO
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (EXAMPLE 30, 200 mg, 0.281 mmol), methyl hydroxyacetate (0.022 mL, 0.281 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (81 mg, 0.422 mmol) and triethylamine (0.059 mL, 0.422 mmol) were stirred in DCM (2.811 mL) at room temperature overnight. LCMS of aliquot indicated formation of the desired product and complete consumption of starting material. Volatiles were evaporated from the reaction crude. The pot residue was purified by prep HPLC to afford a light yellow solid as the titled compound. LCMS (ESI) calc.=783.19; found=784.0 (M+1)+. 1H NMR (CDCl3, 400 MHz, 1:1 mixture of atropisomers): δ 7.99 (d, J=6.8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.85 (s, 1H), 7.72-7.68 (m, 1.5H), 7.67-7.61 (m, 2.5H), 7.45-7.36 (m, 2H), 7.32-7.26 (m, 1H), 7.13 (s, 1H), 7.08 (d, J=5.6 Hz, 0.5), 7.06 (d, J=5.6 Hz, 0.5H), 5.59 (d, J=8 Hz, 0.5H), 5.30 (d, J=8 Hz, 0.5H), 4.97 (d, J=14 Hz, 0.5H), 4.93 (d, J=14 Hz, 0.5H), 4.87 (s, 2H), 4.16 (d, J=15.6 Hz, 0.5H), 3.95 (d, J=16 Hz, 0.5H), 3.86 (s, 3H), 3.80 (s, 3H), 3.80-3.75 (m, 1H), 2.37 (s, 1.5H), 2.32 (s, 1.5H), 0.54 (d, J=6.8 Hz, 1.5H), 0.42 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: [C:1]([NH:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][C:23]([OH:31])([CH2:24]3)[CH2:22]1)[CH2:28]2)([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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1.CO>C1COCC1>[C:1]([NH:20][C:21]12[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][C:23]([O:31][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([C:33]5[O:32][C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=6[N:34]=5)=[CH:42][CH:43]=4)([CH2:29]3)[CH2:22]1)[CH2:30]2)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: OC12CC3CC(C1)CC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)(C3)C2
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C(NC23CC4CC(C2)CC(OCc2ccc(-c5nc6ccccc6o5)cc2)(C4)C3)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
To KH (35%; 0.35 g; 0.003 mole) in THF (8 ml) under N2 and cooled to 0° C. is added N-trityl-3-hydroxytricyclo-[3.3.1.13,7 ]decan-1 -amine (1 g; 0.0025 mole) of all at once. The reaction is stirred for 5 minutes with ice cooling then at room temperature for an hour, developing into a clear yellow solution. Then 4-(benzoxazol-2-yl)benzyl bromide (0.70 g; 0.0025 mole) is added and the reaction cooled in ice for 10 minutes and stirred at room temperature for 4 hours. Methanol is added to quench any KH, then the reaction is filtered and evaporated to dryness. HPLC is used to purify the product (eluting with 10% ethyl acetate/hexane) to obtain N-trityl-3-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-1-amine (m.p. 174°-177° C.) which is used directly in step D.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:25](O)=O>O>[NH:9]1[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]4[NH:23][CH:25]=[N:24][C:19]=4[CH:18]=3)=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: Nc1ccc(-c2nc3ccc(-c4ccc(N)c(N)c4)cc3[nH]2)cc1
Reactant: O=CO
Solvent: O
Product: Nc1ccc(-c2nc3cc(-c4ccc5[nH]cnc5c4)ccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 5.8 %

Procedure:
4-(2-(4-Aminophenyl)-1H-benzo[d]imidazol-6-yl)benzene-1,2-diamine (200 mg, 0.64 mmol) and formic acid (0.24 mL, 6.35 mmol) were dissolved in H2O (2 mL) and the mixture heated to 160° C. for 20 min under microwave irradiation. On cooling, a precipitate formed, which was filtered off and washed with water. The filtrate was basified with K2CO3 and stirred for 30 min by which time a precipitate had formed. The mixture was filtered and the precipitate washed with water and dried under suction. The crude product was purified by column chromatography (EtOAc to 85:15 EtOAc-MeOH) to afford the product as a white solid (12 mg, 6%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][CH2:29][CH2:30][NH2:31])=[N:26][CH:27]=1)([O-:21])=[O:20]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([NH:31][CH2:30][CH2:29][NH:28][C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][N:26]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Product: O=[N+]([O-])c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
In analogy to the procedure for preparing Example 7A, the product is obtained as a solid by reacting 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) with N-(5-nitropyridin-2-yl)ethane-1,2-diamine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15](C(OCC(Cl)(Cl)Cl)=O)[CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(Cl)cc1)C2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C2CC3CCC(N3)C2OCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A suspension of 1.14 g (2.06 mmol) of 2,2,2-trichloroethyl (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate and 400 mg of zinc in 10 ml of acetic acid was stirred at room temperature for 12 hours. The reaction solution was diluted with 50 ml of water and extracted four times with 40 ml of methylene chloride. The organic phase was washed twice with 50 ml of 1 N sodium hydroxide solution, dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 9:1 mixture of methylene chloride and methanol as the eluent. There was obtained 0.480 g (61% of theory) of (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane of m.p. 184-185°; MS: 379 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][CH:44]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:22][CH:21]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:19][C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:43]2[CH:44]=[CH:45][C:46]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]3)=[CH:47][CH:48]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCN1CCC(CO)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCC(CO)CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, (1-propargylpiperidin-4-yl)methanol (122 mg, 0.8 mmol) and diisopropylamine (370 mg, 0.56 mmol) were added to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (220 mg, 0.4 mmol; prepared as described in example 7) in tetrahydrofuran (15 mL). Subsequently, bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) and copper(I) iodide (15 mg, 0.075 mmol) were added; the reaction mixture was degassed again and then stirred under inert atmosphere at ambient temperature over night. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a paddle of silica gel. The paddle was thoroughly washed with ethyl acetate (4×20 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 95:5) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-[4-(hydroxymethyl)piperidin-1-yl]propynyl]phenyl]allyloxy]-2-methyl phenoxy]acetate.
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:5](O)=O)=O.ClC(=C)[C:17]#[N:18].[C:20](OC(=O)C)(=O)C>>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[NH:3][CH:1]=[CH:20][C:5]=2[C:17]#[N:18])=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=C(Cl)C#N
Reactant: Cc1ccc(C(NC=O)C(=O)O)cc1
Product: Cc1ccc(-c2[nH]ccc2C#N)cc1
Temperature: 90 °C

Procedure:
To a stirred suspension of 2-formylamino-2-(4-methylphenyl)acetic acid (4.00 g) in acetic anhydride (45 ml) was added 2-chloroacrylonitrile (16.5 ml) at room temperature and the resulting suspension was heated at 90° C. for 2.5 hours. After cooling, the solvent was evaporated and the residue was washed with isopropyl ether. The mixture was filtered and the resulting solid was dissolved into ethyl acetate and the solution was washed with aqueous saturated sodium bicarbonate and water successively. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with n-hexane/methylene chloride 1:3 (V/V) to give 2-(4-methylphenyl)pyrrole-3-carbonitrile (0.73 g) as a colorless viscous oil.