Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH2:1]([C:5]1[N:9]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCc1cc(C(=O)OCC)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cc(C(=O)OCC)cn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Under an argon atmosphere, ethyl 5-butyl-1H-pyrrole-3-carboxylate (976 mg) was dissolved in tetrahydrofuran (50 mL), sodium hydride (60% in oil, 240 mg) was added and the mixture was stirred at room temperature for 30 min. Benzenesulfonyl chloride (0.77 mL) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2), and the obtained solid was washed with hexane to give the title compound as a colorless solid (yield 780 mg, 47%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].C(OCC)(=O)C.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: CNC
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N(C)C
Reaction time: 4 h
Yield: 92 %

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid (1.2, 0.515 g, 2.06 mmol) was dissolved in ethyl acetate (8 mL, 0.08 mol). Dimethylamine (0.4 mL, 0.008 mol) was added next. The reaction was left to stir for 4 hours. The reaction was extracted with 0.5 M HCl, washed with water and brine, and the organic layer dried over magnesium sulfate. The ethyl acetate was evaporated and the crude product 1.3.Af was obtained in 92% yield. MS analysis (m−1)=257.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:18]=1.C([Sn](CCCC)(CCCC)C=C)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH:17]=[CH2:18])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)CCC(=O)OC)nc1
Yield: 15 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (commercially available: 0.25 g, 0.871 mmol) in toluene (10 mL) was added palladium; triphenylphosphane (0.101 g, 0.0871 mmol) and tributyl(vinyl)stannane (0.33 g, 0.30 mL, 1.04 mmol). The reaction mixture was refluxed overnight. Then, 0.05 eq of palladium triphenylphosphane and 0.6 eq of tritutylvinylstannane were added. Volatiles were removed under vacuum and residue taken up in acetonitrile. The acetonitrile phase was washed twice with hexane and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give methyl 4-oxo-4-[(5-vinyl-2-pyridyl)amino]butanoate (compound A40) (0.20 g, 15%). 1H NMR (400 MHz, CDCl3) 8.26 (s, 1H), 8.19 (sb, 1H), 8.15 (m, 2H), 7.76 (m, 1H), 6.65 (m, 1H), 5.34 (d, 1H), 5.30 (d, 1H), 3.72 (s, 3H), 2.75 (m, 4H) ppm.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>[Pd].[C].C(O)C>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1)[CH2:6][O:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)C=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Yield: 100 %

Procedure:
A mixture of ethyl 4-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-2-butenoate (40.00 g, 92.5 mmol), 5% Pd-carbon (1.00 g) and ethanol (250 mL) was stirred for 20 hours at room temperature in a hydrogen atmosphere. After filtering the catalyst, the solvent was evaporated in vacuo to give ethyl 4-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenylbutanoate (40.18 g, 100%) as an oily product. 1H-NMR (DMSO-d6) δ: 1.04 (t, J=7.1 Hz, 3H), 2.60 (dd, J=8.0, 15.5 Hz, 1H), 2.81 (dd, J=6.8, 15.5 Hz, 1H), 3.38-3.45 (m, 1H), 3.65 (d, J=6.9 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 4.65 and 4.66 (ABq, J=14.1 Hz, 2H), 7.20-7.24 (m, 1H), 7.28-7.32 (m, 4H), 7.90 (s, 2H), 7.99 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br>CC(O)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([Br:21])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2ccsc2c(=O)n1Cc1ccccc1
Solvent: CC(=O)O
Product: CCC(Br)c1nc2ccsc2c(=O)n1Cc1ccccc1
Temperature: 60 °C

Procedure:
3-Benzyl-2-propylthieno[3,2-d]pyrimidin-4(3H)-one (1-5, 0.80 g, 2.81 mmol) was dissolved in AcOH (3.0 mL) and treated with Br2 neat 0.43 mL, 8.44 mmol). The reaction was warmed to 60° C. for 6 h, and then concentrated. The residue was purified by flash column chromatography (SiO2, 0-10% EtOAc/hexanes gradient) to give 3-benzyl-2-(1-bromopropyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-6). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=5.2 Hz, 1H), 7.28 (m, 4H), 7.15 (d, J=7.0 Hz, 2H), 6.26 (d, J=16.5 Hz, 1H), 4.93 (d, J=16.5 Hz, 1H), 4.68 (t, J=7.1 H, 1H), 2.43 (m, 1H), 2.25 (m, 1H), 0.73 (t, J=7.0 Hz, 3H); MS 364.8 found 363.2 required.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=O)C.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O.O>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)ccc(N)c1[N+](=O)[O-]

Procedure:
4-(Acetylamino)-2-methylbenzoic acid (3.93 g, 20.3 mmol) was taken up in concentrated sulfuric acid (20 mL) and warmed to solubilize. The solution was then cooled with an ice bath. Fuming nitric acid (0.86 mL) in sulfuric acid (2.0 mL) was added dropwise and the resultant solution was stirred one hour. The solution was then diluted with water and a yellow solid was collected by filtration and discarded. Upon standing, an orange solid formed in the filtrate, which was collected by filtration to give (0.61 g) of 4-amino-2-methyl-3-nitrobenzoic acid. The aqueous filtrate was then extracted (3×100 mL of 10% methanol in ethyl acetate), and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to yield additional 4-amino-2-methyl-3-nitrobenzoic acid (0.90 g). 1H NMR (400 MHz, d6-DMSO): 7.75 (d, 1H), 6.75 (d, 1H), 2.41 (s, 3H). MS (EI) for C8H8N2O4: 195 (MH+).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:39]=[CH:38][C:37](=[O:40])[C:36]([C:41]([NH2:43])=[O:42])=[CH:35]1)(=O)C1C=CC=CC=1>N>[C@H:11]1([N:34]2[CH:39]=[CH:38][C:37](=[O:40])[C:36]([C:41]([NH2:43])=[O:42])=[CH:35]2)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: NC(=O)c1cn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)ccc1=O
Agent: N
Product: NC(=O)c1cn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)ccc1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
Compound 33 (0.5 g, 0.86 mmol) was dissolved in dry methanolic ammonia (50 mL) and stirred for 15 h in a bomb at room temperature. The solution is then concentrated to a small volume and cooled overnight at 4° C. The crystalline product formed was filtered off, washed with cold methanol. The solid was recyrstallized from absolute ethanol to give 0.23 g (87%) of pure product: mp 209-211° C.; 1H NMR (Me2SO-d6) δ3.60 (m, 2H, C5′H), 3.983 (m, 1H, C4′H), 4.09 (m, 1H, C3′H), 4.34 (m, 1H, C2′H), 5.11 (m, 1H, C5′OH, D2O exchangeable), 5.22 and 5.47 (2m, 2H, C2′,3′OH, D2O exchangeable), 5.84 (d, 1H, J1′,2′=6.3 Hz, C1′H), 7.21 (m, 2H, PhH), 7.64 (m, 2H, PhH and CONH2) and 8.44 (s, 1H, CONH2). Anal. Calc. for C11H14N2O6 (270.24): C, 48.89; H, 5.22; N,10.37. Found: C, 48.89; H, 5.42 N, 10.51.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[Br:29])[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Sn](Cl)Cl.C(O)C>O>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([Br:29])=[C:20]([CH:25]=1)[CH2:19][N:15]1[C@@H:14]([CH3:30])[C@@H:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:31])([F:32])[F:1])[CH:4]=2)[O:17][C:16]1=[O:18]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(N)ccc1Br
Temperature: 20 °C
Reaction time: 36 h

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one (614 mg, 1.17 mmol), tin(II) chloride dehydrate (1.314 g, 5.823 mmol) and ethanol (3 mL) was stirred at 20° C. for 36 h. Reaction crude was worked up with water. The resulting mixture was extracted with EtOAc and dried over Na2SO4. The titled compound was obtained as a glassy material after SiO2 purification (Biotage 40+M, gradient, 0% to 35% EtOAc in hexanes). LC-MS: 499.05 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.77 (s, 2H), 7.31 (d, J=8.5, 1H), 6.77 (d, J=2.7, 1H), 6.54 (dd, J=8.5, 2.7 Hz, 1H), 5.69 (d, J=8.0 Hz, 1H), 4.77 (d, J=15.3, 1H), 4.29 (d, J=15.3 Hz, 1H), 4.05-4.12 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[I:25][C:26]1[C:27](CO)=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>C(Cl)Cl>[Br:24][CH2:20][C:27]1[C:26]([I:25])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2ccccc2cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
A solution of triphenylphosphine (469 mg, 1.79 mmol) in dry CH2Cl2 (2 mL) was added dropwise to a stirred solution of carbon tetrabromide (592 mg, 1.79 mmol) and (3-iodo-2-naphthyl)methanol (423 mg, 1.49 mmol) in dry CH2Cl2 (11 mL) at room temperature under N2. The reaction was stirred for 4 h at room temperature and was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to afford 2-(bromomethyl)-3-iodonaphthalene (469 mg, 91%), as a colorless solid. Rf=0.84 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.39 (s, 1H); 7.94 (s, 1H); 7.78-7.76 (m, 1H); 7.71-7.69 (m, 1H); 7.52-7.48 (m, 2H); 4.76 (s, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1.C(N(C(C)C)CC)(C)C>CCCCO>[Br:20][C:18]1[N:19]=[C:14]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][N:3]=[CH:4]3)[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: NCc1ccc2ncncc2c1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1ccc2ncncc2c1
Temperature: 120 °C
Yield: 38.9 %

Procedure:
To the solution of C-quinazolin-6-yl-methylamine (1.2 g, 7.916 mmol) and 2.06 gram of 3,5-dibromo-pyrazin-2-ylamine (2.06 g, 7.916 mmol) in n-BuOH (18 mL) was added diisopropylethylamine (7.0 mL, 40 mmol) at room temperature. The reaction mixture was heated up to 120° C. for two days under nitrogen. The reaction was cooled down, n-BuOH is evaporated directly via rotavapor, followed by purification via a silica gel column to get 5-Bromo-N*3*-quinazolin-6-ylmethyl-pyrazine-2,3-diamine (1.02 g, yield 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:28]=CC)=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:32].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:28]=[O:32])=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC=Cc1c(NC(=O)OC)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc2c(c1C=O)OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of {(2R)-7-[(methoxycarbonyl)amino]-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (5.12 g, 11.8 mmole) in tetrahydrofuran (400 mL) was added 2.42 mL of 4% aqueous osmium tetroxide (0.39 mmole). After 0.5 hour, sodium periodate (12.6 g, 59.1 mmole) in water (100 mL) was added dropwise over a period of 1 hour. The heterogeneous solution was stirred under nitrogen at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum to yield the (R)-enantiomer of the title compound as a light beige solid (4.80 g, 97%).
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)C=CC=CC=1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:20]([O:19][C:17](=[O:18])[NH:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:8]([NH:37][C@@H:34]2[CH2:35][CH2:36][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33]2)=[O:24])[CH2:15][CH2:14]1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)CC1

Procedure:
A solution of (4-tert-butoxycarbonylamino-cyclohexyl)-carbamic acid phenyl ester (1 eq.) and (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) in MeOH is heated using microwave radiation at 100° C. for 30 minutes. The resulting solution is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water 0.1% HCl) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH:7]1OCC[O:8]1.Cl>CC(C)=O>[CH3:1][O:2][C:3](=[O:29])[CH:4]([C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH:7]=[O:8]
Reactant: COC(=O)C(CCC1OCCO1)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)C(CCC=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a magnetically stirred solution of (+/−)-4-[1,3]dioxolan-2-yl-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-butyric acid methyl ester 35b (0.10 g, 0.253 mmol) in acetone (5 mL) at room temperature under Ar atmosphere was slowly added 5N HCl (1.5 mL). The reaction mixture was stirred for 2 h and then concentrated in vacuo to remove acetone. NaHCO3 solution (100 mL) was added until the pH is greater than 9, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to provide 0.064 g (75%) of the crude product. 1H NMR (400 MHz, CDCl3) δ 2.24 (m, 4H), 2.34 (s, 3H), 2.39 (s, 3H), 3.70 (s, 3H), 4.38 (t, J=8.1 Hz, 1H), 7.03 (d, J=1.4 Hz, 1H), 7.24 (d, J=7.3 Hz, 2H), 7.56 (m, 3H), 7.99 (s, 1H), 9.48 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[NH4+].[Cl-]>CO.O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[C:14]([NH2:15])=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2c(cc1N)OCCO2
Yield: 90.5 %

Procedure:
A mixture of 12.0 g (50.2 mmol) of 7-nitro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, 11.2 g (201 mmol) of powdered Fe and 13.3 g (257 mmol) of NH4Cl in 175 ml of MeOH and 70 mL of H2O was refluxed for 5.5 h. An additional 11.2 g of Fe and 13.3 g of NH4Cl was added and the mixture was heated for 5.5 h more. Finally, 5.5 g of Fe and 6.5 g of NH4Cl was added and the mixture was heated for 4 h. The cooled reaction was filtered through Celite, the pad was washed well with MeOH and the filtrate and washings were combined. The solvent was removed and the residue was slurried in H2O and collected. The crude product was filtered through silica (CHCl3) to give 9.5 g of the title compound as tan crystals: mass spectrum (electrospray, m/e): M+H 209.9.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:7])=[CH:4][CH2:5]Br.[CH2:8]([OH:12])[CH:9]([CH3:11])[CH3:10]>>[Br:1][CH2:2][C:3]([CH3:7])=[CH:4][CH2:5][O:12][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CO
Reactant: CC(=CCBr)CBr
Product: CC(=CCOCC(C)C)CBr
Reaction time: 2 h

Procedure:
6.8 g (0.03 mol) of 1,4-dibromo-2-methyl-2-butene are dissolved in 15 cc of isobutanol and 2.9 g (0.03 mol) of sodium isobutylate in 50 cc of isobutanol are added at 0°. After stirring at 0° for 2 hours the mixture is stirred at 20°-25° for 16 hours. The mixture is filtered and the filtrate is evaporated at reduced pressure. The residue is dissolved in ether, washed with saturated salt solution and dried with sodium sulphate. The ether is evaporated and the residue is distilled at 13 mm. The product has a B.P. of 128°-138°/13 mm.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=O.S(=O)(=O)(O)O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][C:17]([C:25]#[N:26])=[C:16]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1.[BH4-].[Na+]>O1CCCC1.CN(C)C=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][C:17]([C:25]#[N:26])=[C:16]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: O=CCCCCl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NCCCCCl
Reaction time: 2 h

Procedure:
To a solution of 1.12 g of 4-chlorobutanal and 5.3 ml of 3M sulfuric acid in 11 ml of tetrahydrofuran, at 0° C., was added an solution of 2.0 g of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-3-quinolinecarbonitrile in 40 ml of dimethylforamide. To this was added portionwise 0.4 g of sodium borohydride. After 1 hr another 1.0 g of aldehyde, 10 ml of dimethylforamide, and 5 ml of 3M sulfuric acid was added followed by the portionwise addition of 0.8 g of sodium borohydride. After 2 hrs, the mixture was poured into water and the Ph was adjusted to 9. The mixture was extracted with ethyl acetate several times. The organic solution was dried over magnesium sulfate and the solvent was removed giving the title compound as an oil which was used without additional purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1ccsc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccsc2)C1=O
Yield: 10 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 3-bromo-thiophene (79.4 mL, 0.8474 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.084 mmol), trans-1,2-diamino cyclohexane (30.5 mL, 0.254 mmol) and potassium carbonate (234 mg, 1.695 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform), followed by preparative HPLC afforded 22 mg of the product (10% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][OH:11])[C:5]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:36])(=[N:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])=[CH:24][CH:23]=1>>[CH2:34]([O:33][C:31]([N:30]=[S:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[CH:4][N:3]=2)=[CH:27][CH:26]=1)([CH3:36])=[O:29])=[O:32])[CH3:35]
Reactant: CC(C)C[C@@H](CO)Nc1nc(Cl)ncc1-c1ccsc1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3ccsc3)c(N[C@H](CO)CC(C)C)n2)cc1
Yield: 42 %

Procedure:
In the reaction (S)-2-(2-chloro-5-thiophen-3-yl-pyrimidine-4-ylamino)-4-methyl-pentan-1-ol (278 mg, 0.89 mmol) with (RS)—S-(4-amino-phenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (240 mg, 0.99 mmol) according to procedure 5b, the desired product is obtained in 42% yield (220 mg) after chromatographic purification (silica gel, dichloromethane/methanol (0%-10% methanol)).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(OC(C)C)(C)C.CCCCCC>>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:8][CH2:9]2)=[O:26])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-N-(4-nitro-phenyl)-2-oxo-acetamide (Example 93) according to the method described in Example 11. Melting Point: 141-143° C. (diisopropylether-hexane).