Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].C(Cl)(Cl)[Cl:74].CO>Cl.C(OCC)(=O)C>[NH:1]([Cl:74])[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNCl)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1

Procedure:
The solution of 100 mg (0.081 mmol) of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14) in 3 ml of hydrogen chloride in ethyl acetate (4 mol/L) was stirred at room temperature for 2 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14). The reaction mixture was evaporated under reduced pressure with ethyl acetate, repeatedly, to remove hydrogen chloride. The residue was triturated with ether to provide the title compound as a colorless powder, which was used for the next reaction directly.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:42]1[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[N:46][CH:47]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:19]=[C:20]([O:22][C:42]3[CH:47]=[N:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc([N+](=O)[O-])nc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 61.5 %

Procedure:
Following the procedure of Example 69(b) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester 0.4 g (0.72 mmol) and 5-bromo-2-nitro-pyridine (0.17 g, 0.86 mmol) were used to afford 0.3 g of the required product. 1H NMR (DMSO-d6): δ 1.31 (18H, d), 1.8 (4H, d), 3.20 (2H, m), 3.8 (2H, m), 4.1 (2H, d), 7.35 (3H, d), 7.4 (3H, m), 7.9 (1H, d), 8.35 (2H, d), 8.5 (1H, s).
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:17][CH:18]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[N:10]=2.C(N(CC)CC)C.Cl[C:27]1[N:36]=[C:35]([NH:37][CH3:38])[C:34]2[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1>C(O)CCC>[N:8]1[C:7]2=[CH:17][CH:18]=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][C:9]=1[N:11]1[CH2:16][CH2:15][N:14]([C:27]2[N:36]=[C:35]([NH:37][CH3:38])[C:34]3[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=3)[N:28]=2)[CH2:13][CH2:12]1
Reactant: Clc1ccc2nc(N3CCNCC3)nc-2cc1
Reactant: CNc1nc(Cl)nc2cc(OC)c(OC)cc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CNc1nc(N2CCN(c3nc4cccccc-4n3)CC2)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A mixture of 2-(1-piperazinyl)cycloheptimidazole hydrochloride (1.5 g, described in Example 1) and triethylamine (1.0 g) in butanol (150 ml) was stirred at room temperature for 15 min and 2-chloro-4-methylamino-6,7-dimethoxyquinazoline (1.53 g) was added. The mixture was refluxed for 22 hr, cooled and filtered. The precipitate was washed and dried to give 2.18 g of the title compound. This compound was dissolved in methanol and the solution was acidified with hydrogen chloride. The precipitate was collected, washed with diethyl ether and crystallized from water-methanol to obtain the dihydrochloride salt of the title compound: mp>250° C.; ir (nujol mull) 3000 cm-1 ; uv max (MeOH) 345 (ε=22,000), 257 nm (ε=54,500) and 245 nm (ε=55,200); nmr (DMSO-d6) δ 3.07 (d, 3H), 3.88 (s, 6H), 4.18 (s, 8H) and 8.0 (s, 7); and Anal. Calcd for C23H25N7O2.2HCl. H2O: C, 53.90% H, 5.46% N, 19.14% Cl, 13.86% and Found: C, 53.82% H, 5.68% N, 19.47% Cl, 13.1%.
Reaction SMILES: COCC(Cl)=O.N1(CCCN)C=CN=C1.[N:16]1([CH2:21][CH2:22][CH2:23][NH:24][C:25](=O)[CH2:26][O:27][CH3:28])[CH:20]=[CH:19][N:18]=[CH:17]1.B>>[N:16]1([CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: COCC(=O)NCCCn1ccnc1
Agent: B
Agent: COCC(=O)Cl
Agent: NCCCn1ccnc1
Product: COCCNCCCn1ccnc1

Procedure:
The reaction of 2-methoxyacetyl chloride and 3-(1H-imidazol-1-yl)propanamine in the presence of triethylamine leads to the formation of N-(3-(1H-imidazol-1-yl)propyl)-2-methoxyacetamide, which by reduction with borane gives N-(3-(1H-imidazol-1-yl)propyl)-2-methoxyethylamine. The latter amine reacts with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol, under the conditions of Example 55 to yield the title compound.
Reaction SMILES: C([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[O:11]1[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[NH:8][CH2:9][CH2:10]1
Reactant: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)NCCO2
Reaction time: 18 h
Yield: 16.3 %

Procedure:
To a solution (2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (520 mg, 1.0 mmol) in methanol (5 mL) was added 10% palladium on charcoal (150 mg), 0.05 mL conc. HCl and the mixture was stirred under hydrogen balloon pressure for 18 h. The reaction mixture was filtered through a celite bed, and the celite was washed with methanol. The resulting filtrate was concentrated to a residue which was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (70 mg).
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CS(OCCCC1CCCC1)(=O)=O>>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:23][CH2:24][CH2:25][CH:20]3[CH2:19][CH2:18][CH2:22][CH2:21]3)[CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: BrCCc1ccccc1
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: CS(=O)(=O)OCCCC1CCCC1
Agent: Cl
Product: Fc1cc(N2CCN(CCCC3CCCC3)CC2)ccc1OCc1ccccc1

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (368 mg) and 3-cyclopentylpropyl methanesulfonate (319 mg), respectively, to provide crude 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclopentylpropyl)piperazine (505 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of 4.2 (0.052 g, 0.11 mmol) in THF (2.00 mL) and EtOH (2.00 mL) at 23° C. was added 1N lithium hydroxide (2.00 mL, 2.00 mmol). Stirring continued for 16 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give compound 4 as a clear oil (0.0466 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (1H, d, J=8.2 Hz), 7.41 (1H, dd, J=8.2, 2.0 Hz), 7.30 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=2.0 Hz), 7.00 (1H, t, J=8.8 Hz), 6.93 (2H, d, J=8.6 Hz), 6.86 (1H, m), 6.80 (1H, dd, J=5.9, 3.3 Hz), 5.00 (2H, s), 4.06 (1H, m), 3.80 (3H, s), 2.81 (1H, dd, J=15.6, 8.4 Hz), 2.72 (1H, dd, J=15.6, 6.6 Hz), 1.84 (3H, d, J=2.3 Hz), 1.24 (9H, s). MS ESI (neg.) m/e: 947.3 (2M−H)+, 473.2 (M−H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].CN(C)C=O.[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>COC(C)(C)C.O>[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: O=Cc1cccc(OCCCOCc2ccccc2)c1

Procedure:
To a 3-L reaction vessel was charged and stirred cesium carbonate (209.6 g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL) and 3-bromopropyl phenylmethyl ether (113.4 g) at ambient temperature for ˜18 h. Water (567 mL) was added followed by tert-butyl methyl ether (907 mL). The bottom aqueous layer was separated and the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL). The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added and the solution concentrated to a minimum and filtered though a 1-μm filter.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[C:14]1([C:20]2NN=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C:20]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Yield: 82 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (6.81 g), 5-phenyl-1H-tetrazole (5.01 g) and pyridine (10 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration, and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with cold hexane to give methyl 4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzoate (7.88 g, yield 82%). Recrystallization from hexane-tetrahydrofuran gave colorless crystals. melting point: 172–173° C.
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([NH2:71])[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:64])[CH3:63])=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:73]1([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH:78]=[CH:77][C:76]([CH:79]2[CH2:83][CH:82](OC)O[CH:80]2OC)=[CH:75][CH:74]=1.FC(F)(F)C(O)=O.C(OC(=O)[C@H](N1C=CC(C2C=CC(C3C=CC=CC=3)=CC=2)=C1)CC(N[C@H](C(=O)N(OC)C)CC(C)C)=O)C1C=CC=CC=1>ClCCCl>[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([N:71]1[CH:82]=[CH:83][C:79]([C:76]2[CH:77]=[CH:78][C:73]([C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[CH:74][CH:75]=2)=[CH:80]1)[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:63])[CH3:64])=[O:58])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Agent: CON(C)C(=O)[C@H](CC(C)C)NC(=O)C[C@H](C(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18), 12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3 (R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (CDCl3) δ 7.62 (d, 2H, J=7.4 Hz), 7.58 (s, 3H), 7.44 (t, 2H, J=7.7 Hz), 7.35-7.21 (m, 7H), 7.10 (s, 1H), 6.80 (t, 1H, J=2.2 Hz), 6.60 (bs, 1H), 5.17-1.13 (m, 1H), 5.10 (s, 2H), 4.97-4.92 (m, 1H), 3.77 (s, 3H), 3.44 (dd, 1H, J=5.7, 17.1 Hz), 3.17 (s, 3H), 3.03 (dd, 1H, J=8.8, 16.5 Hz), 1.67-1.36 (m, 3H), 0.92 (d, 3H, J=6.25 Hz), 0.87 (d, 3H, J=6.3 Hz). Anal. Calculated for C35H39N3O5: C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH:16](O)[CH2:17][CH2:18]CCC3C=CC=CC=3)[C:6](=[O:28])[N:5]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:4]=2[N:3]=1.BrCCCC[N:39]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40]1=[O:51].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][N:39]3[CH2:43][CH2:42][CH:41]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:40]3=[O:51])[C:6](=[O:28])[N:5]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:4]=2[N:3]=1
Reactant: O=C1C(Cc2ccccc2)CCN1CCCCBr
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CC(O)CCCCc1ccccc1)c(=O)n2CCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCCN1CCC(Cc3ccccc3)C1=O)c(=O)n2CCCCC
Temperature: 50 °C
Yield: 86 %

Procedure:
Prepared as with 8-chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione using 1-(4-bromobutyl)-3-(phenylmethyl)-2-pyrrolidinone as the alkylating agent, potassium carbonate as base and heating at 50° C. for 18 h. Yield 86%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:15]([C:16](OC)=O)=[CH:14][N:13]=1.[C-:26]#[N:27].[K+]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[CH:14][C:15]([CH2:16][C:26]#[N:27])=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1
Reactant: [C-]#N
Reactant: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(=O)OC)cn1
Agent: [K+]
Solvent: CO
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CC#N)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(bromomethyl)-2-[2-(3-methoxypropyl)phenyl]-4-(trifluoromethyl)pyridine (1 eq.) from step 1 and KCN (5 eq.) in MeOH (0.08M) was stirred for 48 h at room temperature. The mixture was concentrated and purification by column chromatography on silica gel, eluting with Hex/EtOAc 30%, afforded the title desired material as an off-white solid.
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([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O: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:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)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 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C36H44N7O4Cl2 [(M+H)+] 708.2827, observed 708.2830.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9]
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(Br)c(N)c1
Yield: 94.4 %

Procedure:
The title compound was prepared using the method of example 32, starting with 1-bromo-4-methyl-2-nitro-benzene (Lancaster, 10.1 g, 46.7 mmol), tin chloride dihydrate (Aldrich, 52.8 g, 233 mmol). 8.2 g (94%) of crude compound 244 was obtained as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:38])[C@@H:29]([NH2:37])[CH2:30][C:31]1[S:32][C:33]([Br:36])=[CH:34][CH:35]=1>>[CH3:26][O:27][C:28](=[O:38])[C@@H:29]([NH:37][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[CH2:30][C:31]1[S:32][C:33]([Br:36])=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)s1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid was coupled with (S)-2-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.34 min. MS (ESI−): mass calcd. for C23H18BrClN4O5S2, 607.96; m/z found, 607/609 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.31 (s, 1H), 8.94 (d, J=1.8, 1H), 8.91 (d, J=1.8, 1H), 8.59 (dd, J=7.4, 1.4, 1H), 8.32 (dd, J=8.4, 1.3, 1H), 7.89 (dd, J=8.4, 7.4, 1H), 7.80 (d, J=2.0, 1H), 7.27 (d, J=8.4, 1H), 6.96 (dd, J=8.4, 2.0, 1H), 6.86 (d, J=3.7, 1H), 6.57 (br d, J=6.8, 1H), 6.48 (d, J=3.6, 1H), 4.92 (dt, J=7.0, 4.6, 1H), 3.83 (s, 3H), 3.40 (d, J=4.6, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:12]([NH2:14])=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)C.C(OCC)(OCC)OCC.[OH-].[NH4+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:16][CH2:15][C:11]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH:25]=[N:14][C:12]2=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: O
Product: Cc1cccc(N2C=NC(=O)C23CCN(Cc2ccccc2)CC3)c1

Procedure:
To a mixture of 1-benzyl-4-(3-methylphenylamino)-isonipecotamide (4.3 g, 13.5 mmol) and glacial acetic acid (1.0 mL) in toluene (20 mL) heated under reflux, triethyl orthoformate (2.0 g, 13.5 mmol) was added over a period of 3 h using a syringe pump. The resultant mixture was refluxed for 38 h., and treated with a mixture of concentrated ammonium hydroxide (1.3 mL) and water (3.4 mL). The organic extract was isolated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:17].[K+]>>[NH2:1][C:2]1[C:15]2[C:14](=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Nc1cccc2c1Cc1ccccc1C2=O
Agent: [K+]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 39 %

Procedure:
6.3 g of 4-aminoanthrone are dissolved in 100 ml of hot 1 N KOH. Air is then passed through the solution at 80° C until the yellow exudation from a spot test has disappeared. After filtering off and washing until neutral, 4.5 g of product containing 58.2% of 1-aminoanthraquinone (39% yield) are obtained. On boiling with toluene, which dissolves the 1-aminoanthraquinone, a yellow residue is obtained which according to analysis, NMR-spectrum, IR-spectrum, mass spectrum and molecular weight determination is 4,4' -diamino-dihydrodianthrone (melting point: 251°-253° C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.ClCCl.[Br:29]Br>>[Br:29][C:20]1[C:21]([NH2:24])=[N:22][CH:23]=[C:18]([C:16]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:25])[CH:17]=2)[CH:19]=1
Reactant: BrBr
Reactant: Nc1ccc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)cn1
Solvent: ClCCl
Product: Nc1ncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 429 mg (1.22 mmol) 5-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-2-ylamine in 5 ml dichloromethane 195 mg (1.84 mmol) sodium bicarbonate was added. Then 94 μl (1.84 mmol) bromine were added slowly. The reaction mixture was stirred for 1 hour at room temperature and subsequently was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated yielding 3-bromo-5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-2-ylamine as brown amorphous solid; HPLC-MS: 2.18 min, [M+H] 431.