Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13](C4C=CC(/C=C/C(O)=O)=CC=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.C([C:64]1[CH:65]=[C:66]([CH:70]=[CH:71][CH:72]=1)[C:67]([OH:69])=[O:68])=O>>[CH:30]1([CH2:29][N:10]2[C:11]([NH2:12])=[C:15]([NH2:14])[C:16](=[O:17])[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]2=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1.[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:65]4[CH:64]=[CH:72][CH:71]=[CH:70][C:66]=4[C:67]([OH:69])=[O:68])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1
Yield: 85 %

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (2.00 g) and immediately condensed with 3-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367–3370) to give title compound as an off-white solid (2.27 g, 85%), m.p. >250° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>ClCCl>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:22][CH2:23][C@H:24]([NH:27][C:37]([N:36]([CH3:40])[CH3:35])=[O:38])[CH2:25][CH2:26]2)[CH2:15][CH2:14]1
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c(Cl)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(CC[C@H]3CC[C@H](NC(=O)N(C)C)CC3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.92 g (2 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (60 ml), triethylamine (1.26 ml, 9 mmol) was added followed by 0.21 ml (2.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature. The solution was washed with water (2×10 ml), dried and evaporated in vacuo. Purification with flash chromatography gave 0.66 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, melting at 196-8° C. This product was dissolved in dichloromethane (60 ml), then 6.4 ml (6.4 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added, followed by 25 ml saturated NaHCO3 solution. After separation the organic layer was dried and evaporated in vacuo. Purification with flash chromatography gave 0.4 g of the title compound, melting at 278-80° C.
Reaction SMILES: [N:1]([CH:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:7][CH2:6][CH:5]1[OH:19])=[N+:2]=[N-:3].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([CH:4]1[CH:5]([O:19][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:9]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=NC1C=C(c2ccncc2[N+](=O)[O-])CCC1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccncc2[N+](=O)[O-])=CC1N=[N+]=[N-]
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of (+/−)-2-azido-4-(3-nitropyridin-4-yl)cyclohex-3-enol (1.0 equiv.) in DCM (0.15M) was added TBSCl (2.0 equiv.), imidazole (2.0 equiv.) and DMAP (0.1 equiv.) at room temperature. After 18 h, water was added, the organics were dried with brine, then Na2SO4, and concentrated. The crude material was loaded to silica gel and purified via ISCO eluting with ethyl acetate and hexanes (20%). Obtained (+/−)-4-(3-azido-4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)-3-nitropyridine as a yellow oil in 60% yield. LCMS (m/z): 376.3 (MH+), LC Rt=5.848 min.
Reaction SMILES: N1(C2NC=CN=2)CCCCC1.N1([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)C=CN=C1.[F:39]C1C=CC(C(C2CCNCC2)=O)=CC=1>>[F:39][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(c1ccc(-n2ccnc2)cc1)C1CCN(CCc2ccccc2)CC1
Agent: c1c[nH]c(N2CCCCC2)n1
Product: O=C(c1ccc(F)cc1)C1CCN(CCc2ccccc2)CC1

Procedure:
For example if the desired piperidinyl imidazole derivative of Formula I is [4-(1H-imidazol-1-yl)phenyl][1-(2-phenylethyl)-4-piperidinyl]methanone; then 4-fluorophenyl-4-piperidinyl methanone is reacted with 1-halo-2-phenylethane thereby producing the intermediate of Formula IV, 4-fluorophenyl[1-(2-phenylethyl)-4-piperidinyl]methanone.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CC(C)([O-])C.[K+]>O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([NH:3][CH2:2][CH2:1][NH2:4])[CH:7]=1
Reactant: Clc1cccnc1
Reactant: NCCN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: NCCNc1cccnc1
Temperature: 118 °C

Procedure:
A mixture of 1.32 g of ethylenediamine, 250 mg of 3-chloropyridine, and 740 mg of potassium tert-butoxide was heated at 118° C. in a sealed tube for 18 hrs. The reaction was cooled to room temperature, diluted with water and extracted with chloroform. The organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title product as a red oil. MS (M+H)+=137.9.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:21][C:20]1[C:16]([C:11]2[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([N:8]([S:28]([CH3:27])(=[O:30])=[O:29])[S:28]([CH3:27])(=[O:30])=[O:29])[CH:10]=2)=[N:17][N:18]([CH3:26])[C:19]=1[O:22][CH:23]([F:24])[F:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c(Cl)c1OC(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(-c2ccc(Cl)c(N(S(C)(=O)=O)S(C)(=O)=O)c2)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g (22 mmol) of triethylamine were added to a solution of 3 g (10 mmol) of 3-(3-amino-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 50 ml of dichloromethane. 2.5 g (21 mmol) of methanesulfonyl chloride were added dropwise to this mixture at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then washed with water. The organic phase was subsequently dried over magnesium sulfate and concentrated. The solid product was washed with a little diethyl ether. Yield: 3.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][C:22]=2[Cl:24])[N:6]=1)=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)cc1N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (3 g, 10.03 mmol), 2,4-dichlorophenylboronic acid (2.297 g, 12.04 mmol), potassium phosphate (4.26 g, 20.06 mmol) and Fibrecat® 1034A (Johnson Matthey, polymer supported palladium complex) (500 mg, 10.03 mmol) were suspended in toluene (50 ml) and water (15 ml). The reaction mixture was heated to 110° C. under vigorous stirring for 3 hours. The mixture was allowed to cool to RT and EtOAc (100 ml) was added. The organic layer was separated and washed with brine (15 ml). MP-TMT (macroporous polystyrene-bound trimercaptotriazine, 3 g, Polymern labs) was added and stirred for 1 hour at RT. MgSO4 was added and the suspension filtered off. The filtrate was concentrated in vacuo and purification of the residue by reverse phase chromatography (130 g C18 column) eluting with water/MeOH afforded the title compound as a white solid; LS-MS Rt=1.55 mins [M+H]+ 365 (Method 2 minLC_v002).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][N:29]([C:1]([Cl:4])=[O:2])[CH2:28][CH2:27]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Cl)Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Temperature: 0 °C
Yield: 51 %

Procedure:
To a −78° C. solution of 1.85 M phosgene in toluene (15.8 mL, 29.3 mmol) and DCM (32 mL) was added 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (4.00 g, 14.6 mmol), prepared as described in Example 1d, in one portion with stirring, followed immediately by the rapid addition of DIEA (2.66 mL, 16.1 mmol) along the walls of the flask over ˜5 sec. The flask was sealed and stirred at −78° C. for another 5 min before placing the flask in an ice bath with stirring at 0° C. for 30 min. The opaque easily stirred slurry was then poured into a mixture of DCM (70 mL), 0.5 M trisodium citrate (60 mL), and ice (60 mL), and partitioned. The aqueous layer was extracted with DCM (1×50 mL) and the organic layers combined, dried (Na2SO4), and concentrated under reduced pressure to give the crude title compound as an orange solid. Purification by flash chromatography (7:1→4:1 DCM/acetone) afforded the title compound as a beige solid (2.50 g, 51%). 1H-NMR (300 MHz, CDCl3) 9.07 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 4.58-4.47 (m, 2H), 4.072 (s, 3H), 4.068 (s, 3H), 3.65 (tt, J=10.9 Hz, 4.0 Hz, 1H), 3.46-3.33 (m, 1H), 3.28-3.14 (m, 1H), 2.30-2.06 (m, 2H), 2.06-1.95 (m, 2H). LC/MS (ESI): calcd mass 335.1, found 336.1 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)[CH2:4][C:3]1=[O:13].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH:5]([C:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[CH:4]([Br:15])[C:3]1=[O:13]
Reactant: BrBr
Reactant: CC1(C)C(=O)CC1c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)C(Br)C1c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
2.08 g (0.01 mol) of 2,2-dimethyl-3-(4-chlorophenyl)cyclobutanone are dissolved in 30 ml of chloroform, and a solution of 1.6 g of bromine in 5 ml of chloroform is added dropwise. After stirring for one hour at 20° C., the solvent is distilled off under waterpump vacuum. 2.6 g of crude 2,2-dimethyl-3-(4-chlorophenyl)-4-bromocyclobutanone are obtained as a residue which is employed further without further purification (compare: Example 1).
Reaction SMILES: [Na].[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([C:13]([OH:15])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3].Cl[CH2:23][C:24]#[N:25]>CN(C)C=O>[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([C:13]([O:15][CH2:23][C:24]#[N:25])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3]
Reactant: CCn1ncc2nc(C(=O)O)c(-c3ccccc3)nc21
Reactant: N#CCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCn1ncc2nc(C(=O)OCC#N)c(-c3ccccc3)nc21

Procedure:
5.8 g. of the sodium salt of 1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.02 mol.), 1.7 g. of chloroacetonitrile (0.22 mol.) and 70 ml. of dry dimethyl-formamide are heated in an autoclave at 120° for 5 hours. After vacuum removal of the solvent, the residual 1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid, cyano-methyl ester is treated with water, filtered off, again treated with alcohol and then recrystallized from ethanol, yield 3.9 g. (64%), m.p. 102°-103°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][O:28][CH:29]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccoc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and 3-furanylboronic acid (54 mg, 0.48 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was purified by SCX followed by mass directed autoprep HPLC to afford the title compound (E118). MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: [C:1]1([N:11]2[CH:15]=[N:14][NH:13][C:12]2=[S:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])=[O:20].N1C=CC=CC=1>CS(C)=O.O>[C:1]1([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[S:16][CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)Nc1ccccc1[N+](=O)[O-]
Reactant: S=c1[nH]ncn1-c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(CSc1nncn1-c1cccc2ccccc12)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 2.2 %

Procedure:
A solution of 2,4-dihydro-4-(1-naphthalenyl)-3H-1,2,4-triazole-3-thione (129 mg, 0.50 mmol) in DMSO (2 mL) was added slowly to a solution of 2-bromo-N-(2-nitrophenyl)acetamide (113 mg, 0.50 mmol) and pyridine (121 μL, 1.49 mmol) in DMSO (1 mL) at room temperature. The mixture was stirred at room temperature for 18 h, then diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (3×) and brine, dried (MgSO4), filtered and concentrated under reduced pressure. A mixture of Et2O and hexane (1:1) was added, the resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC using a gradient of MeCN/H2O containing TFA (0.06%) (CombiPrep ODS-AQ 50×20 mm, 5μ, 120 Å). The pure fractions were combined and concentrated to give the title compound (4.5 mg, 2% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:19][CH2:18][NH:17][CH2:16][C:6]=2[C:7]2[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:17]2[CH2:18][CH2:19][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]4[NH:11][C:10](=[O:14])[C:9](=[O:15])[NH:8][C:7]=4[C:6]=3[CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CNCC3
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccc(Cl)cc1)N1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Yield: 104.4 %

Procedure:
The 7-nitroquinoxalinedione from Example 31 (100 mg, 0.38 mmol) was treated with the CDI adduct of 4-chlorobenzoic acid (0.57 mmol) by a procedure similar to that in Example 32 to give a yellow solid (159 mg, 99% yield). mp=280-283° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][OH:19])=[CH:12][C:11]=1[O:20][CH2:21][CH:22]([CH3:24])[CH3:23].[CH:25]1([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36](O)[CH:35]=2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:25]1([CH:28]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([O:19][CH2:18][C:13]3[C:14]([O:16][CH3:17])=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:12]=3)[CH:39]=2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:27]1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2nc(OC)c(CO)cc2OCC(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)nc2OC)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-isobutoxy-2-methoxypyridin-3-yl)methanol (94 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (62 mg) in toluene (4.0 mL) were added 1,1′-(azodicarbonyl)dipiperidine (113 mg) and tributylphosphine (112 μL), and the mixture was stirred at room temperature for 14 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (120 mg) as a colorless oil.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].C1CCN2C(=NCCC2)CC1.CS(O)(=O)=O>C(O)C.O>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CNC(N)=S
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cn1c(S)nc(-c2ccncn2)cc1=O
Temperature: 0 °C
Yield: 77.9 %

Procedure:
A solution of ethyl 3-oxo-3-(4-pyrimidyl)propionate (34.1 g, 176 mmol), N-methyl thiourea (47.5 g, 527 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (26.3 ml, 176 mmol) in ethanol (340 ml) was refluxed for 2 hours and the solution of methanesulfonic acid (16.9 g, 176 mmol) in water (70 ml) was added after cooling by ice-water. The precipitate was washed with water, filtered and dried to give the title compound (30.2 g, 78%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)C=[N:32][CH:31]=1>O1CCOCC1>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:37]4[CH:36]=[C:35]5[CH:34]=[CH:39][NH:30][C:31]5=[N:32][CH:38]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: c1ccc2ncncc2c1
Reactant: c1ccc2c(c1)CCCN2
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)CCCN2c1ncnc2ccc(-c3cnc4[nH]ccc4c3)cc12
Yield: 43 %

Procedure:
0.50 g of 4-chloro-6-iodoquinazoline, 0.30 g of 1,2,3,4-tetrahydroquinoline and 0.40 ml of triethylamine in 4 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of column chromatography (gradient heptane: EA 5-100% in 16 min.), giving 0.27 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline as yellow solid (yield 43%, content 96%); MS-FAB (M+H+)=387.8; Rf (polar method): 2.43 min.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 83 %

Procedure:
Diphenyl N-(Boc-D-Phe-Pro)amino(4-amidinophenyl)-methanephosphonate hydrochloride {Boc-D-Phe-L-Pro-(4-AmPhGly)P (OPh)2 }. Boc-D-Phe-OH (2.66 g, 10 mmole) and L-Pro-OBzl (2.42 g) were coupled using DCC, and Boc-D-Phe-Pro-OBzl was obtained in 83% yield; 1H NMR (CDCl3) δ 7.34 (s, 5H), 7.23 (m, 5H), 5.4 (d, 1H), 5.15 (q, 2H), 4.65 (m, 1H), 4.35 (m, 1H), 3.5 (m, 1H), 3.1-2.9 (m, 2H), 2.6 (m, 1H), 2.-1.7 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].C(C1C(C(F)(F)F)=CC=CC=1O)C=C.[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: C=CCc1ccc(C(F)(F)F)cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: C=CCc1c(O)cccc1C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1ccc(C(F)(F)F)cc1O
Yield: 87.5 %

Procedure:
A mixture of 2-allyl-5-trifluoromethyl-phenol (60 mg, 12%) and 2-allyl-3-trifluoromethyl-phenol and 10% Pd/C (20 mg) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 2-propyl-5-trifluoromethyl-phenol (53 mg, 87%).