Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.CSC(=N)N[N+]([O-])=O.S1C=CCN1CSC[CH2:27][NH:28][C:29]([NH:31][N+:32]([O-:34])=[O:33])=N.CNC(=N[N+]([O-])=O)SC>>[S:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH3:27])=[N:31][N+:32]([O-:34])=[O:33])=[N:7]1
Reactant: NCCSCc1ccsn1
Reactant: N=C(NCCSCN1CC=CS1)N[N+](=O)[O-]
Agent: CNC(=N[N+](=O)[O-])SC
Agent: CSC(=N)N[N+](=O)[O-]
Product: CNC(=N[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(2-isothiazolylmethylthio)ethyl]-N'-nitroguanidine and reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-methyl-N"-nitroguanidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OC)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.FC1C=CC([C:37]([NH:39][C:40]2[S:41][C:42]3[C:48](N4CCOCC4)=[CH:47][CH:46]=[C:45]([O:55][CH3:56])[C:43]=3[N:44]=2)=[O:38])=CC=1>>[N:13]1([C:48]2[C:42]3[S:41][C:40]([NH:39][C:37](=[O:38])[C:7]4[CH:2]=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][CH:6]=4)=[N:44][C:43]=3[C:45]([O:55][CH3:56])=[CH:46][CH:47]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C1CCCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(N2CCCCCC2)c2sc(NC(=O)c3ccc([N+](=O)[O-])cc3)nc12

Procedure:
The title compound was prepared using 4-bromo-1-methoxy-2-nitro-benzene, azepane and 4-nitro-benzoyl chloride as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=427 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]1=2.CO>[Pd].O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:15]1[CH2:16][CH:12]([OH:11])[CH:13]=[CH:14]1
Reactant: C1CC2=C(C1)O2
Reactant: Clc1ncnc2nc[nH]c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OC1C=CC(n2cnc3c(Cl)ncnc32)C1
Yield: 25 %

Procedure:
Trimethylsilylated 6-chloropurine (prepared from 50 g (0.32 mol) of 6-chloropurine) is stirred with 5 mol % of the palladium(0) catalyst described above and an equivalent amount of epoxycyclopentene in tetrahydrofuran at room temperature for 24 hours. The reaction solution is heated with methanol for 1.5 hours, the precipitate formed is filtered off with suction, the resulting solution is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 20/1. 18.9 g (25% of theory) of 6-chloro-9-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]purine (Example 1.5.1.) are obtained as yellowish crystals of melting point 118° C. 1H-NMR (270 MHz, d6 -DMSO), δ[ppm]: 8.80 (s, 1H), 8.62 (s, 1H), 6.25 (m, 1H), 6.08 (m, 1H), 5.60 (m, 1H), 5.31 (d, 1H), 4.76 (m, 1H), 2.95 (m, 1H), 1.81 (m, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[N:28]=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]2[CH2:36][NH:35][CH2:34][CH2:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C.O.[Pd+2]>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[N:28]=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]2[CH2:36][N:35]([C:7]3[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=3[CH3:16])[CH2:34][CH2:33][C:31]=2[N:32]=1
Reactant: Cc1ccc(C(C)C)cc1OS(=O)(=O)C(F)(F)F
Reactant: COCCCOc1nc(-c2c(C)cccc2C)nc2c1CNCC2
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCOc1nc(-c2c(C)cccc2C)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Temperature: 140 °C

Procedure:
To 5-isopropyl-2-methylphenyl trifluoromethanesulfonate, prepared as described in Example 15 (153 mg, 0.541 mmol) in a microwave vial was added a solution of 2-(2,6-dimethylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine in THF (4 mL). Next, Cs2CO3 (235 mg, 0.721 mmol) was added and the reaction mixture was degassed via a series of argon/vacuum cycles. The reaction mixture was then charged with chloro(2-dicyclohxylphosphino-2′,4′,6%-triisopropyl-1,1′-biphenyl)-[2-(2-aminoethyl)phenyl)]-palladium(II) (CAS#1028206-56-5, 26.6 mg, 0.036 mmol). The vessel was then sealed and heated via microwave irradiation at 140° C. for 90 minutes. The reaction was then cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The organic layers were combined, dried over Na2SO4 filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (5-50% ethyl acetate/heptanes) to provide 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 1.25 (d, J=7.1 Hz, 6 H) 2.08 (quin, J=6.3 Hz, 2 H) 2.28 (s, 6 H) 2.49 (s, 3 H) 2.92 (dt, J=13.8, 6.9 Hz, 1 H) 3.28 (s, 3 H) 3.49 (t, J=5.9 Hz, 2 H) 3.58 (t, J=5.7 Hz, 2 H) 3.81 (t, J=5.6 Hz, 2 H) 4.37 (s, 2 H) 4.71 (t, J=6.4 Hz, 2 H) 7.12 (dd, J=7.7, 1.4 Hz, 1 H) 7.17 (s, 1 H) 7.20-7.27 (m, 3 H) 7.36-7.41 (m, 1 H); MS (ESI+) m/z 460.4 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][PH:5](=[O:7])[O-:6])(=O)C.[Na+:8].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16](O)C>>[CH3:16][P:5]([C:4](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:1])(=[O:7])[O-:6].[Na+:8]
Reactant: CCO
Reactant: CC(=O)C[PH](=O)[O-]
Reactant: Nc1ccccc1
Agent: [Na+]
Product: CC(=Nc1ccccc1)P(C)(=O)[O-]
Reaction time: 72 h

Procedure:
A mixture of sodium acetylmethylphosphinate (4.3 g) and aniline (3.2 ml) was dissolved in ethanol (200 ml) and allowed to stand for 72 hours over 4 A molecular sieve. The solution was filtered free of the solid phase, evaporated in vacuo and the residue was triturated with ether to give a pale brown solid (6.1 g). The nmr spectrum showed that the crude product contained an aromatic moiety.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH2:25][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:24]=[C:20]2[C:19]([CH3:45])=[CH:18][N:17]=1>>[CH3:15][C:16]1[N:21]2[N:22]=[C:23](/[CH:25]=[CH:7]/[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[N:5]=3)[N:24]=[C:20]2[C:19]([CH3:45])=[CH:18][N:17]=1
Reactant: Cn1nc(N2CCCC2)nc1C=O
Reactant: Cc1cnc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Product: Cc1cnc(C)n2nc(/C=C/c3nc(N4CCCC4)nn3C)nc12
Yield: 50.1 %

Procedure:
Was prepared in the same manner as described in Example 81a) using 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (30 mg, 166 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (76.4 mg, 166 μmol, Eq: 1.00) (prepared as described in WO2011150156, pp 123-125, Expl. 24 g) affording 5,8-dimethyl-2-[(E)-2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-[1,2,4]triazolo[1,5-c]pyrimidine (27 mg, 50.0%) as light yellow amorphous. MS: m/z=325.6 (M+H+)
Reaction SMILES: C[C:2]1([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[CH2:5][C:4]=2[CH2:3]1.[CH2:17]([O:19][C:20](=[O:33])[CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][CH:26]=1)=[O:24])[CH3:18].N1CCCC[CH2:35]1>C(O)C>[CH2:17]([O:19][C:20](=[O:33])[CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([S:12](=[O:13])(=[O:14])[NH:15][CH3:16])[C:3]=3[CH3:35])[NH:7][C:6]2=[O:11])[NH:27][CH:26]=1)=[O:24])[CH3:18]
Reactant: CCOC(=O)CNC(=O)c1c[nH]c(C=O)c1C
Reactant: C1CCNCC1
Reactant: CNS(=O)(=O)C1(C)C=CC2=C(CC(=O)N2)C1
Solvent: CCO
Product: CCOC(=O)CNC(=O)c1c[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)c(C)c32)c1C
Yield: 52 %

Procedure:
5-Methyl-5-methylaminosulfonyl-2-oxindole (50 mg, 0.21 mmol) was condensed with [(5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino]-acetic acid ethyl ester (100 mg, 0.42 mmol) and piperidine (0.1 mL) in ethanol (2 mL) to give 50 mg (52%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>N1C=CC=CC=1.CC(C)=O.C(Cl)Cl>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:8]2[S:7][C:6]3[C:17]4[C:22]([CH:23]=[CH:24][C:5]=3[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3](=[O:30])[C@@H:2]2[O:1][C:36](=[O:37])[C:35]2[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:14][CH:13]=1
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 17 h
Yield: 55.6 %

Procedure:
To a solution of 1.50 g (0.0035 mol) of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one, in 20 ml of dry pyridine was added dropwise 1.4 g (0.0059 mol) of 3,4,5-trimethoxybenzoyl chloride at ice-bath temperature. The mixture was stirred at this temperature for 17 hours and concentrated to dryness. The residue was partitioned between methylene chloride and dilute ammonium hydroxide. The methylene chloride extracts were washed with brine and dried (MgSO4). Removal of the solvent gave a residue, which was dissolved in a mixture of acetone-methylene chloride (70:30) and chromatographed on 40 g silica gel. The column was eluted with 50 ml portions of acetone-methylene chloride (70:30). Fractions 4-15 were combined and the solvent was removed under reduced pressure to give 1.3 g of crude product, which after crystallization from ethanol afforded 1.2 g (55%) of (±)-cis-2,3-dihydro-2-(4-methoxyphenyl)-3 -[(3,4,5-trimethoxybenzoyl)oxy]-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one, mp 189°-190°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:15]=3)=[C:9]([N+:31]([O-])=O)[CH:8]=2)[CH:4]=[N:3]1.[CH3:34]OC(OC)OC.C(O)=O>CO.[Zn]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]3[N:13]([C:14]4[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:15]=4)[CH:34]=[N:31][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: COC(OC)OC
Reactant: COC(=O)c1sc(Nc2ccc(-c3cnn(C)c3)cc2[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Zn]
Solvent: CO
Solvent: O=CO
Product: COC(=O)c1sc(-n2cnc3cc(-c4cnn(C)c4)ccc32)cc1OCc1ccccc1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
Methyl 5-{[4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl]amino}-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate (1.0 g, 2.2 mmol) from a different batch than that made in Step A3, was dissolved In MeOH (30 mL). Trimethylorthoformate (6.0 mL, 54 mmol) was added followed by formic acid (0.81 ml, 21.5 mmol). Zinc dust (0.70 g, 11 mmol) was added and the reaction mixture was heated to 70° C. for 2 h and then cooled to rt. The reaction mixture was filtered through a pad of celite which was then washed with 20% MeOH/DCM. The crude reaction mixture was concentrated to remove the MeOH and the remaining mixture was poured into half-saturated aqueous NaHCO3 solution and then extracted with a mixture of 4:1 DCM:i-PrOH. The combined organics were dried over anhydrous MgSO4 and purified by flash chromatography to give 850 mg (89%) of the title compound, methyl 5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate. MS (ESI): 445 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Br:14])=[O:23]
Reactant: O=C=Nc1ccccc1Br
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-bromophenyl isocyanate (0.30 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 4 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-bromophenyl)ureido]phenylacetate (770 mg, 73%) as a pale brown powder. 1H-NMR (CDCl3) δ3.55 (s, 2H), 3.70 (s, 3H), 6.97 (dd, J=7.3, 1.5 Hz, 1H), 7.22 (dd, J=8.5, 2.2 Hz, 1H), 7.29-7.33 (m, 2H), 7.48 (d, J=1.0, 2.2 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 8.01 (m, 2H); MS (ESI) m/z 443 (M++1), 445 (M++3), 447 (M++5).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl.O>CN(C=O)C>[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COCCOCCl
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
3.8 g (0.13 mol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen and a solution of 40 g (0.13 mol) of 2-(1-adamantyl)-4-bromophenol in 100 ml of DMF was added dropwise. The mixture was stirred until the evolution of gas had ceased. A solution of 18 ml (0.15 mol) of 2-methoxyethoxymethyl chloride in 20 ml of DMF was then added dropwise and the mixture was stirred for four hours at room temperature. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (50/50). After evaporation of the solvents, 40.1 g (78%) of the expected compound, having a melting point of 69°-70° C., were recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:37]1([C:43]#[CH:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1.[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:44]#[C:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(I)cc2)n1C(=O)OC(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(C#Cc3ccccc3)cc2)n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-tert-butoxycarbonylamino-5-(4-iodophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.100 g, 0.206 mmol) was dissolved in anhydrous THF (8 mL) and to this solution was added DIPEA (0.359 mL, 2.06 mmol), CuI (0.004 g, 0.021 mmol), and PdCl2(PPh3)2 (0.014 g, 0.021 mmol). The solution was then degassed at ambient temperature for 10 minutes. During this time a solution of the phenyl acetylene (0.105 g, 1.03 mmol) in anhydrous THF (3 mL) was also degassed. The solution of alkyne was added drop-wise to the solution of aryl iodide and the reaction was stirred at room temperature for 12 h. The reaction was filtered through a Celite® pad and the filter cake rinsed with EtOAc (10 mL). The filtrate was washed with sat. NH4Cl (2×10 mL), brine (2×10 mL), and dried (Na2SO4). Filtration and evaporation afforded the crude product which was purified via flash column chromatography (10-50% EtOAc/Hexanes) to obtain 0.085 g (90%) of the target 2-tert-butoxycarbonylamino-5-(4-phenylethynylphenyl) imidazole-1-carboxylic acid tert-butyl ester as a yellow solid: mp=131-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.00 (s, 1H), 7.86 (d, 2H, J=7.6 Hz), 7.42-7.57 (m, 7H), 1.58 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 152.9, 146.8, 139.9, 136.3, 133.0, 131.7, 131.4, 128.8, 124.9, 122.4, 126.8, 120.9, 113.7, 89.9, 89.5, 85.4, 80.1, 27.9, 27.3; HRMS (ESI) calcd for C27H19N3O4Na (MNa+) 482.2050. found 482.2051.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH3:9])=[C:6]([CH3:10])[N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(C#N)c(O)nc1C
Product: Cc1cc(C#N)c(Cl)nc1C
Yield: 53.6 %

Procedure:
An intimate mixture of 3-cyano-5,6-dimethyl-2-hydroxypyridine (42 g) and phosphorus pentachloride (81 g) was heated at 140°-160° for 2 hours. Phosphoryl chloride was removed by distillation under reduced pressure and ice-water (500 g) was added to the residue. The mixture was adjusted to pH 7 with aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to an oil which was crystallised from ether/petroleum ether (b.p. 60°-80°) to give 2-chloro-3-cyano-5,6-dimethylpyridine (25.3 g) m.p. 83°-87°.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:19]=[C:18]3[C:13]([NH:14][C:15](=[O:25])[C:16]([C:20]([O:22]CC)=[O:21])=[N:17]3)=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].S(=O)(=O)(O)O>>[N:1]1([CH:6]([C:10]2[CH:19]=[C:18]3[C:13]([NH:14][C:15](=[O:25])[C:16]([C:20]([OH:22])=[O:21])=[N:17]3)=[CH:12][CH:11]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C(c1ccc2[nH]c(=O)c(C(=O)O)nc2c1)n1ccnc1
Yield: 24.6 %

Procedure:
A solution of 4.25 parts of ethyl 3,4-dihydro-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]3-oxo-2-quinoxalinecarboxylate in 20 parts of a sodium hydroxide solution 1N was stirred for 4 hours at room temperature. The reaction mixture was treated with a diluted sulfuric acid solution to pH 5.5. After concentration, the residue was crystallized from pyridine. The product was filtered off and dried, yielding 1 part (24.6%) of 3,4-dihydro-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]-3-oxo-2-quinoxalinecarboxylic acid; mp. 237.5° C. (comp. 129).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:18][CH:19]=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH3:9].[C:27]1([N:24]2[CH2:23][CH2:22][N:21]([CH2:17][CH2:18]/[CH:19]=[CH:20]\[C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:12][C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[N:9]=4)=[CH:4][CH:3]=3)[CH2:26][CH2:25]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCCN1CCN(c2ccccc2)CC1
Reactant: Brc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C(=C\c1ccc(-c2nc3ccccc3[nH]2)cc1)\CCN1CCN(c2ccccc2)CC1
Product: N
Yield: 30.4 %

Procedure:
A mixture of 2-(4-bromophenyl)-1H-benzimidazole (Example F) (8.08 g), 1-but-3-enyl-4-phenylpiperazine (Example G) (8.0 g), palladium acetate (0.66 g), tri-o-tolylphosphine (1.8 g) and triethylamine (7.05 g) in acetonitrile (100 mL) is stirred at reflux for 2 hours. The mixture is cooled and filtered through Celite. The filtrate is evaporated to leave a brown solid. This solid is purified by MPLC on silica gel eluting with 100:8:1 dichloromethane: ethanol: 0.880 aqueous ammonia to give 1.84 g of the title compound as a white solid; mp 140°-145° C.
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][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[S:56]1[CH:60]=[CH:59][N:58]=[C:57]1[NH2:61]>CN(C=O)C.O>[C:16]([O:15][C:13](=[O:14])[NH:1][C@H:2]([C:10](=[O:12])[NH:61][C:57]1[S:56][CH:60]=[CH:59][N:58]=1)[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of Boc-Cha-OH (9.2 g, 34 mmol), DIEA (15 ml, 85 mmol) and BOP (16.5 g, 37 mmol) in DMF (80 ml) was maintained at ambient temperature for 40 minutes followed by the addition of thiazol-2-ylamine (3.4 g, 34 mmol). Reaction was maintained at ambient temperature for 2 hours. Reaction mixture was diluted with water (200 ml) and extracted with EtOAc (2×150 ml). Organic layer was washed with brine (100 ml), dried over anh. MgSO4 and evaporated in vacuum. Residue was subjected to flash chromatography on CombiFlash® Companion unit equipped with RediSep® flash column (normal phase, 35-60 micron average particle size silicagel, 40 g, Teledyne Isco); flow rate=35 ml/min; injection volume 2 ml; mobile phase A: hexane; mobile phase B: EtOAc; gradient 0-70% B in 1 h. Fractions containing the desired product were combined and concentrated in vacuum to provide target compound (8.89 g, 74%) as yellow oil. LC-MS [M+H] 354.4 (C17H27N3O3S+H, requires 354.49).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][CH2:13][CH2:14][NH:15][C:1](=[O:3])[CH3:2])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(CCCN)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(CCCNC(C)=O)OCC

Procedure:
20 g (196 mmol) of acetic anhydride in 100 ml of benzene are added, drop by drop, at reflux to a stirred suspension of 32 g (198 mmol) of 4,4-diethoxybutylamine and 24 g (174 mmol) of potassium carbonate in 600 ml of benzene. The mixture is heated to reflux for 15 min. and cooled, the precipitate is filtered and the filtrate is evaporated to dryness. The residual oil is treated with vegetable charcoal in 300 ml of diethyl ether and, after filtration and evaporation of the filtrate in vacuo, 37.3 g (183 mmol) of oily product are obtained. n20D =1.4472.