Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[O:30]=[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][NH:32]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[O:12][C:11](=[O:29])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[CH:36][C:31](=[O:30])[NH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Reactant: O=c1ccc(B(O)O)c[nH]1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.37 min, m/z=474(M+1); 1H NMR (CDCl3) 7.97, (dd, 1H), 7.73(s, 1H), 7.33(m, 2H), 7.20(d, 2H), 7.17(t, 2H), 6.98(m, 3H), 5.67(q, 1H), 3.00(dt, 1H), 2.49(m, 2H), 2.30(m, 1H), 2.13(s, 2H), 1.55(d, 3H), 1.45(s, 3H), 1.34(s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[CH:13][C:14]#[N:15])[CH:5]=[CH:4][C:3]1=2.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][C:30](O)=[O:31])(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:14]([CH:13]=[CH:12][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH:28]([NH:27][S:24]([C:19]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=1)(=[O:26])=[O:25])[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:11][CH2:10][CH2:9]2)#[N:15]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Reactant: N#CC=Cc1ccc2c(c1)CCCC2N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: N#CC=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-acrylonitrile (100 mg, 0.504 mmol) in CH2Cl2 (10 mL) was added 3-(3,4-dichlorobenzene-sulfonylamino)-3-(4-fluoro-phenyl)-propionic acid (210 mg, 0.554 mmol), HATU (96 mg, 0.252 mmol), EDC (106 mg, 0.55 mmol), and DIEA (0.17 mL, 1.008 mmol). The resulting mixture was stirred at RT for 18 h. Solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with Hex:Acetone mixture (75:25) gave final compound. MS m/z: 573.12 (M+H). Calc'd. for C28H24Cl2FN3O3S-572.48.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[NH:14][NH2:15].CN(C)[CH:18]=[C:19]([S:23][C:24]([F:27])([F:26])[F:25])[C:20](=O)[CH3:21]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=[C:5]([Cl:13])[C:4]=1[N:14]1[C:20]([CH3:21])=[C:19]([S:23][C:24]([F:27])([F:26])[F:25])[CH:18]=[N:15]1
Reactant: CC(=O)C(=CN(C)C)SC(F)(F)F
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Product: Cc1c(SC(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of 29 g (0.1 mol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine hydrochloride and 21 g (0.1 mol) of 1-dimethylamino-2-trifluoromethylthio-but-1-en-3-one in 150 ml of ethanol is stirred for 16 hours at 70° C. to 75° C. The mixture is worked up by concentrating in vacuo, the residue is taken up in chloroform, washed with water, dried over sodium sulphate and concentrated in vacuo, and the residue is distilled in a high vacuum. 26 g (61% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethylthiopyrazole of boiling point 140° C. at 0.02 mbar and of melting point 54° C.-56° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[C:19]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[CH:28]1([O:27][C:19]2[CH:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:34][C@H:35]([OH:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:13]=3)[CH:22]=[CH:21][C:20]=2[CH2:23][C:24]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(CC(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(CC(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Reaction time: 1.5 h
Yield: 23.6 %

Procedure:
To a solution of [4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]acetic acid (228 mg) in N,N-dimethylformamide (2.5 ml) was added 1,1′-carbonyldiimidazole (77 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 1.5 hours. To this one were added methanesulfonamide (76 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (91 mg) at 5° C., and the mixture was stirred at the same temperature for 5 hours. The resulting mixture was poured into 1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid (twice) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=10:1 to 5:1) to give tert-butyl [2-(3′-(cyclohexyloxy)-4′-[2-[(methylsulfonyl)amino]-2-oxoethyl]-4-biphenylyl]ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (61 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=3)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[CH3:42][CH:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:44].CCN(C(C)C)C(C)C.[I-].[Na+].C[Si](C)(C)[O-:64].[K+]>CC#N.C1COCC1>[CH:32]([OH:31])=[O:64].[CH3:42][CH:43]([N:45]1[CH2:50][CH2:49][N:48]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:47][CH2:46]1)[CH3:44]
Reactant: CC(C)N1CCNCC1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Reactant: C[Si](C)(C)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4CCN(C(C)C)CC4)n3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Product: O=CO
Temperature: 70 °C
Yield: 43.6 %

Procedure:
2-(Chloromethyl)-N-[6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.08 mmol) was dissolved in MeCN (0.5 ml). 4-(1-Methylethyl)piperazine (13 mg, 0.1 mmol) was dissolved in MeCN (0.3 ml) and added to the mixture, followed by DIPEA (0.026 ml, 0.15 mmol) and sodium iodide (0.012 g, 0.078 mmol) (heaped microspatula). The solution was stirred and heated to 70° C. for 18 hr. Potassium trimethylsilanolate (64 mg, 0.5 mmol) was dissolved in THF (0.4 ml) and added to the mixture which was then heated at 50° C. for 5 hrs. The solution was quenched with aqueous MeCN (50:50, 1 ml) and neutralised, then the solvents were removed in a blowdown unit. The residue was dissolved in DMSO 0.5 ml and purified by MDAP (Method D). The solvent was evaporated using the Genevac to give the title compound (11 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: N#CC1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 92.6 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), piperidine-4-carbonitrile (3.03 g, 27.50 mmol) and DIPEA (5.66 mL, 32.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and the residue was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidine-4-carbonitrile (6.86 g, 93%) as a cream crystalline solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33](=[N:42][C:43]#[N:44])OOC3C=CC=CC=3)[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3].OC[CH2:47][NH:48]C.[CH:50]([OH:53])(C)[CH3:51]>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33]([N:48]([CH2:51][CH2:50][OH:53])[CH3:47])=[N:42][C:43]#[N:44])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CNCCO
Reactant: CC(C)O
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCCc1nc2c(C)cc(NC(=NC#N)N(C)CCO)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 6d from 4'-[[2-n-propyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and N-(2-hydroxy-ethyl)-methylamine in isopropanol.
Reaction SMILES: CC(N=NC(C#N)(C)C)([C:4]#[N:5])C.C1C(=O)N(Br)C(=O)C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:47]=[O:48])=[CH:24][CH:23]=1.CN>C(Cl)(Cl)(Cl)Cl.CO>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[C:47](=[O:48])[NH:5][CH3:4])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CN
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)OC)c3)cc12
Reaction time: 0.5 h
Yield: 210.7 %

Procedure:
AIBN (4.6 mg, 0.028 mmol) and NBS (21.6 mg, 0.121 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (35 mg, 0.093 mmol) in CCl4 (5 mL) at 95° C. It was allowed to stir for 30 min and then allowed to cool and was then treated with methanamine (0.466 mL, 0.932 mmol, 2M in THF) and the reaction was allowed to stir for 10 min then diluted with MeOH. A ppt formed which was filtered away and the filtrate was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=320 nm) to give to give the expected product methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (24 mg, 0.059 mmol, 64% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.60 (1H, d, J=2.14 Hz), 8.44 (1H, d, J=2.44 Hz), 8.32 (1H, s), 8.10 (1H, d, J=7.93 Hz), 7.95-8.00 (2H, m), 7.84 (1H, d, J=7.63 Hz), 7.59 (1H, t, J=7.78 Hz), 7.22-7.26 (2H, m), 5.91 (1H, br. s.), 3.98 (3H, s), 3.03 (3H, d, J=4.88 Hz). LC-MS retention time: 1.46 mM; m/z (MH+): 405. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 mM, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:42][CH2:43][O:44][C:45]([CH3:47])=[O:46]>C(#N)C.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>[NH2:14][C:15]1[CH2:16][C:17]([C:27](=[O:28])[N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:8]3[CH:7]=[CH:6][C:5]([CH2:3][CH2:47][C:45]([O:44][CH2:43][CH3:42])=[O:46])=[CH:10][CH:9]=3)=[CH:22][C:20]=2[N:21]=1
Reactant: CCOC(C)=O
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(CCC(=O)OCC)cc3)cc2N=C(N)C1
Temperature: 100 °C

Procedure:
(27%) was prepared as follows, substituting ethyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. 1H NMR (400 MHz, CDCl3) δ 7.57-7.60 (m, 2H), 7.49-7.51 (m, 1H), 7.25-7.35 (m, 4H), 6.84 (s, 1H), 5.22 (very broad singlet, 1H), 4.11-4.17 (m, 2H), 3.41-3.51 (m, 4H), 2.95-3.04 (m, 2H), 2.83 (s, 2H), 2.64-2.69 (m, 2H), 1.58-1.72 (m, 4H), 1.20-1.30 (m, 3H), 0.88-0.99 (m, 6H); m/z (APCI-pos) M+1=462.3.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([CH:14]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)[OH:15])[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1>CO.[Pd]>[ClH:1].[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[C:12]([CH:14]([C:16]3[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=3)[OH:15])=[CH:13][CH:2]=[CH:3][C:4]=2[CH2:9][O:8]1
Reactant: Cn1cnc(C(O)c2cc(Cl)cc3c2OC(C)(C)OC3)c1
Agent: [Pd]
Solvent: CO
Product: Cl
Product: Cn1cnc(C(O)c2cccc3c2OC(C)(C)OC3)c1

Procedure:
15.88 g of alpha-(6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)-1-methyl-1H-imidazole-4-methanol (prepared as in 4. above), dissolved in 160 ml of methanol, are subjected to hydrogenolysis in the presence of 3 g of 10% palladium on carbon under a hydrogen pressure of 3.5 bars at 50° C. for 150 minutes. The catalyst is then filtered off, the solvent is removed and the residue is stirred in diethyl ether. The ethereal phase is decanted off and the residue obtained is used as such in the following step.
Reaction SMILES: [C:1](=[O:4])(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:17]([C:16]1[C:1]([OH:4])=[N:13][C:12]([NH:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:14][C:15]=1[CH3:21])[CH2:18][CH2:19][CH3:20]
Reactant: N=C(N)Nc1ccccc1
Reactant: Cc1ccccc1
Reactant: O=C(O)O
Solvent: O
Product: CCCCc1c(C)nc(Nc2ccccc2)nc1O
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Phenylguanidine carbonate (13.5 g, 100 mmol), β-keto esters (22.3 g, 120 mmol) and 120 mL of toluene were added to 250 mL of flask in sequence, the mixture was heated to reflux with a Dean Stark trap until all the water was removed, and continue refluxing for half an hour. After most of solvent was removed, the reaction solution was cooled to room temperature, the solid was filtered, washed with 20% ethanol aqueous solution and dried to obtain 18.3 g of white solid (II-1) with yield of 71.2%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:22])([C:17](OCC)=[O:18])[C:12](OCC)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:22])([CH2:17][OH:18])[CH2:12][OH:13]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
To a solution of diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (7.5 g, 20.0 mmol) in anhydrous tetrahydrofuran (80 mL) was slowly added a solution of lithium aluminum hydride (22 mL, 22.0 mmol, 1.0 M in THF) at 0° C. under an atmosphere of nitrogen. After stirring for 10 minutes the reaction was completed. The reaction mixture was quenched by the slow addition of methanol at 0° C. The reaction mixture was then partitioned between dichloromethane and 1 N hydrochloric acid. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc 2:1) to give 2-(2-bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (1.4 g, 24%) as a red solid. 1H NMR (400 MHz, DMSO-d6) S 8.31 (d, J=2.4 Hz, 1H), 8.13 (dd, J=2.4, 8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 4.74 (t, J=5.2 Hz, 2H), 3.93 (q, J=5.2 Hz, 2H), 3.79 (m, q, J=5.2 Hz, 2H), 1.38 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1–2% MeOH—CHCl3) to afford the title compound E24 as an off-white solid (0.20 g, 58%). mp 142–144° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B═CH3CN], Gradient elution program: T/% B=0/20, 10/20,25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 40.56 min, 98.60% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH2:13].[N+:14]([C:17]1[CH:18]=[C:19]2[C:30](=O)[O:29][C:27](=[O:28])[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=1)[C:20]2=3)([O-:16])=[O:15]>C(N(CCO)C1C=CC(N2C(=O)C3C=CC([N+]([O-])=O)=C4C=3C(=CC=C4)C2=O)=CC=1)C>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[N:13]1[C:30](=[O:29])[C:19]2[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:26]=[C:25]3[C:20]=2[C:21](=[CH:22][CH:23]=[CH:24]3)[C:27]1=[O:28]
Reactant: COc1ccc(N)c(NCCO)c1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Agent: CCN(CCO)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1
Product: COc1ccc(N2C(=O)c3cccc4cc([N+](=O)[O-])cc(c34)C2=O)c(NCCO)c1

Procedure:
The reaction of N-(2-hydroxyethyl)-5-methoxy-2-aminoaniline with 3-nitronaphthalene-1,8-dicarboxylic anhydride in imidazole (synthesis and work-up as in Example 2, Step 1) afforded the product as a dark-red powder. For purification, the crude product in ethanol/acetone was filtered through a bed of silica gel UV/Vis (CHCl3: λmax: 411, 524 nm
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H][H].[Br:17][C:18]([CH3:23])([CH3:22])[C:19](Br)=[O:20]>>[C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[NH:1][C:19](=[O:20])[C:18]([Br:17])([CH3:23])[CH3:22])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1sccc1C(=O)c1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Reactant: [H][H]
Product: CC(C)(Br)C(=O)Nc1sccc1C(=O)c1ccccc1
Yield: 86 %

Procedure:
1.0 g 2-Amino-3-benzoyl-thiophene (compound 3 wherein R3 is hydrogen) was acylated with 2-bromo-2-methylpropanoyl bromide to give 1.49 g (86%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CC[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1CCN(Cc2ccccc2)C[C@H]1COc1ccccc1F
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 32 %

Procedure:
After dissolving 1.49 g of cis-1-benzyl-4-hydroxy-3-(p-toluenesulfonyloxymethyl)piperidine in 8 ml of N,N-dimethylformamide, 0.71 ml of 2-fluorophenol and 1.22 g of anhydrous potassium carbonate were added and the mixture was stirred at 100° C. for 50 minutes. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a 5N sodium hydroxide solution, water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (402 mg, 32% yield).