Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30].[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1cnccn1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2cnccn2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 33 %

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyrazin-2-yl)pentanoate (1.5 eq., prepared in Synthetic Example 7) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyrazin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 33%). The product was purified through flash column chromatography and recrystallization (mp 194–195° C./DMF).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+].[CH3:26][N:27]([CH2:37][CH:38]=O)[S:28]([C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1)(=[O:30])=[O:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[CH3:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([N:18]3[CH2:23][CH2:22][N:21]([CH2:38][CH2:37][N:27]([CH3:26])[S:28]([C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)(=[O:30])=[O:29])[CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: CN(CC=O)S(=O)(=O)c1cnn(C)c1
Reactant: COCc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COCc1ccc(-c2nccnc2N2CCN(CCN(C)S(=O)(=O)c3cnn(C)c3)CC2)cc1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Cool a suspension of 3′-(4-methyoxymethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (23.62 g, 66.11 mmol) in 1,2-dichloroethane (500 mL) at 5° C. Treat with 1.0 M NaOH (141 mL, 141 mmol), separate layers, dry the organics over Na2SO4, filter, then add to a solution of 1-methyl-1H-pyrazole-4-sulfonic acid methyl-(2-oxo-ethyl)-amide (17.66 g, 81.29 mmol) in 1,2-dichloroethane (1 L). Cool the reaction mixture to 5-10° C., treat with sodium triacetoxyborohydride (29.50 g, 132.2 mmol), and stir at room temperature overnight. Recool the reaction to 5° C., treat with 5 M NaOH (200 mL), and separate the resulting layers. Extract the aqueous layer with CH2Cl2 (500 mL), combine the organics, dry over Na2SO4, filter and concentrate. Dissolve the crude material in MeOH/EtOAc, treat with activated carbon (50 g) at room temperature for 1 hr., then filter through celite and concentrate to provide the free base of the title compound as an oil (29.8 g, 93%). Cool anhydrous EtOH (100 mL) to 5° C. and then add dropwise acetyl chloride (4.45 mL, 61.39 mmol). Stir the resulting solution at room temperature for about 15 min., then add it dropwise to a solution of the above free base dissolved in anhydrous EtOH (800 mL). Stir at room temperature for 0.5 hr., then concentrate in vacuo to ca. 20% of the original volume. Treat the resulting oil/solid with EtOAc (1.5 L). Recover the resulting yellow solid by vacuum filtration and dry in vacuo to provide the title compound (27.28 g, 85.2%). MS ES: m/z=486 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-])=[CH:7][C:6]=2[N:16]=1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>C(Cl)(Cl)Cl>[NH2:47][C:7]1[C:6]2[N:16]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [4-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in chloroform was added p-toluene sulfonyl chloride (1.2 eq.) followed by aq.ammonium hydroxide solution. The resulting reaction mixture was stirred at room temperature for overnight. Reaction mixture was washed with saturated sodium bicarbonate solution. Organic layer separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield sticky solid, which was then purified using silica gel column chromatography to afford tert-butyl [4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.[C:17]([NH2:20])(=[S:19])[CH3:18]>C(O)C>[CH3:18][C:17]1[S:19][C:2]([CH3:16])=[C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[N:20]=1
Reactant: CC(N)=S
Reactant: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2
Solvent: CCO
Product: Cc1nc(-c2ccc3c(c2)CCC(=O)N3)c(C)s1
Reaction time: 0.5 h

Procedure:
A mixture of 6-(α-bromopropionyl)-3,4-dihydrocarbostyril (7 g), thioacetamide (2 g) and absolute ethanol (250 ml) is stirred under reflux for 3 hours and allowed to cool overnight. The resulting white precipitate is filtered, washed with ether, dried and suspended in aqueous sodium bicarbonate for 30 minutes. The neutralized solid is filtered, washed with water, isopropanol, and recrystallized from isopropanol affording the desired product, M.P. 241°-242° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]=[S:7]1(=[O:32])[CH:12]=[CH:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25]C(=O)C(F)F)[O:21][C:20]3=[O:31])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>N1C=CC=CC=1.ClCCl>[O:32]=[S:7]1(=[O:6])[CH:8]=[CH:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:2](=[O:3])[O:4][CH3:5])[O:21][C:20]3=[O:31])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Methyl chloroformate (0.072 mL, 0.925 mmol) is added dropwise at 0° C. to to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.881 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is allowed to warm to room temperature, stirred for 1 hour, and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give white solid (0.26 g, 78%). M.p. 196–7° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](=O)[CH3:7])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:16][S:19][C:6]=1[CH3:7])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)=C(N)c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)nsc1C
Yield: 39.7 %

Procedure:
To a solution of the 2-(amino-phenyl-methylene)-3-oxo-butyric acid ethyl ester (41 g, 170 mmol) in toluene (340 mL) were added P2S5 (117.3 g, 520 mmol) and tetrachloro-1,4-benzoquinone (43.2 g, 170 mmol) at r.t. with stirring. The mixture was then refluxed with stirring for 15 min. After cooling to r. t. the mixture was filtered and the filtrate was concentrated to give a brown oil, which was purified by flash column chromatography on silica gel. Elution with 5-35% EtOAc/hexanes gave the title compound as a reddish oil (16.7 g): MS (m/z) 248.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2].[H-].[Na+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2]
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(CN2CC[C@H](N(Cc3ccccc3)S(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
N-Cbz-7-aminonaphthalene-2-sulfonic acid-[1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.56 g, 1.01 mmol) is dissolved in 10 mL of DMF and cooled to 0° C. Sodium hydride (42 mg of a 60% dispersion in mineral oil, 1.06 mmol) is added and the solution is stirred for 20 minutes. To the mixture is added benzyl bromide (0.18 g, 1.06 mmol). The reaction mixture is stirred at 0° C. for 20 minutes and then at room temperature for 1.5 hours. The solution is poured into a separatory funnel and diluted with 100 mL of EtOAc. The organic layer is washed with water, 1 N HCl and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to give the title compound (0.34 g, 0.53 mmol) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](O)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:29]([N:28]([CH3:32])[CH3:27])=[O:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 140 °C
Yield: 6.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (39 mg, 0.15 mmol), potassium carbonate (32 mg, 0.30 mmol) and dimethylcarbamyl chloride (27 μL, 0.30 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 afforded 3 mg (29%) of 3-(2-pyridyl)-5-(3-cyano-5-(dimethylamino)carbonylphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.85 (d, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 7.89 (m, 1H), 7.73 (s, 1H), 7.48 (dd, 1H), 3.14 (s, 3H), 3.06 (s, 3H).
Reaction SMILES: [Na+].[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2ncccc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(C2=NS(=O)(=O)c3ncccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.9 %

Procedure:
The crude (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid sodium salt (·0.928 mmol), (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.27 g, 0.928 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.494 g, 1.3 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (2 mL). The mixture was stirred at 25° C. for 1.5 h. Triethylamine (0.697 mL, 5 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with ethyl acetate (˜15 mL) and the product solidified. The solid was collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.03 g, 0.064 mmol, 6.9%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.92-1.05 (2H, m), 1.18-1.46 (4H, m), 2.26 (1H, d, J=3.1 Hz), 2.36 (1H, d, J=9.5 Hz), 2.45 (1H, d, J=3.0 Hz), 3.15 (1H, d, J=9.4 Hz), 4.13 (1H, d, J=15.6 Hz), 4.86 (1H, d, J=15.6 Hz), 7.01-7.05 (2H, m), 7.16-7.20 (2H, m), 7.39-7.42 (1H, m), 7.50 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 8.26 (1H, dd, J1=4.6 Hz, J2=1.5 Hz). LC-MS (ESI) calcd for C23H21FN4O4S 468.13. found 469.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(Nc2ccc(C=O)cc2[N+](=O)[O-])nc1-c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3nc(-c4ccc(Cl)cc4)c(C(N)=O)s3)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
To a mixture of 0.10 g (0.24 mmole) of 4-(4-chloro-phenyl)-2-(4-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.18a), 0.31 g (1.44 mmole) of sodium triacetoxyborohydride and 5 mL of dichloromethane was added 0.04 mL (0.36 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature for 4 hours and then diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-15:85) to give 0.044 g of 4-(4-chloro-phenyl)-2-[4-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.18b).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(S(C1C=C(C2C=C(CN(C)C)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: C1COCCN1
Agent: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN3CCOCC3)cc3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 133 and morpholine according to the procedure outline for the preparation of Compound 134. 1H NMR (400 MHz, CD3OD) δ 8.42 (br s, 1H), 8.24 (s, 1H), 8.14 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6 Hz), 7.97 (s, 1H), 7.90 (t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.48 (s, 1H), 4.62 (s, 2H), 4.00-4.09 (m, 2H), 3.71-3.80 (m, 2H), 3.41-3.50 (m, 2H), 3.27-3.32 (m, 4H), 2.39 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C25H27N3O3S, 450; found 450.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 mL dichloromethane is cooled in an ice bath. Then 7.54 g tert-butyldimethylsilyl chloride in 20 mL dichloromethane are added followed by 9.8 mL triethylamine and 0.5 g 4-dimethylaminopyridine. The resultant solution is stirred for 16 h at ambient temperature and then diluted with 100 mL dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulfate. After the solvent is removed, the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[S:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[S:8][C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]([CH2:5][C:1]#[N:2])[C:10]=2[CH:11]=1
Reactant: Clc1ccc2sc(-c3ccccc3)c(CBr)c2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.2 eq. of NaCN are suspended in 20 ml of dimethyl sulphoxide. The mixture is heated at 60° C. for 30 minutes and then 1 eq. of the compound obtained in Step C is added gradually. The reaction mixture is stirred for 1 hour at 60° C. and is then hydrolysed. Extraction with ethyl acetate is carried out and the organic phase is washed with water, dried over MgSO4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([F:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH:21]=[C:20]([C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[C:5]([F:11])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(Br)c2ccoc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c3occc23)CC1
Temperature: 85 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
A mixture of commercially available 4-bromo-7-fluoro-benzofurane [CAS-No 1194376-46-9] (0.72 g, 3.35 mmol) and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.09 g, 3.52 mmol) in 1,2-dimethoxyethane (22 ml) and 2M sodium carbonate solution (5.58 ml, 11.2 mmol) was purged with argon in an ultrasonic bath during 5 min. Then triphenylphosphine (176 mg, 0.67 mmol) and palladium(II)acetate (75.2 mg, 0.34 mmol) were added and the reaction mixture was allowed to stir at 85° C. for 5 h. The reaction mixture was cooled to room temperature, poured into water (50 ml) and extracted with diethyl ether (2×120 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product (1.7 g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate, 0-50%) to yield 4-(7-fluoro-benzofuran-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow oil (0.97 g, 91%), MS (ISP) m/z=262.1 [(M+H)+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8](N)[C@@H:7]([O:13][CH3:14])[CH2:6]2.ClC1C=C2C(=CC=1)C(=[O:25])CC2.COC(OC)OC.CC1C=CC(S(OI(O)C2C=CC=CC=2)(=O)=O)=CC=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:25])[CH:7]([O:13][CH3:14])[CH2:6]2
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Agent: Cl
Solvent: COC(OC)OC
Product: COC1Cc2cc(Cl)ccc2C1=O

Procedure:
Scheme 3 describes the preparation of (1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (20) which is further exemplified in Example 4 below. 5-chloro-2,3-dihydro-1H-inden-1-one (17) was reacted with trimethylorthoformate under acidic conditions, followed by treatment with Koser's reagent [PhI(OH)(OTs)] to give 5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-one (18). The indenone was treated with (R)-tert-butyl sulfinamide in the presence of titanium tetraethoxide to afford the corresponding sulfinamide (19). The reaction was allowed to proceed until less than 5% of the undesired diastereoisomer could be detected by HPLC. The crude sulfinamide was reduced using NaBH4 to afford the primary amine which was treated with hydrochloric acid to afford (1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (20).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:17]=1)[O:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9]1>CO.[Ni]>[NH2:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=1[O:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9]1
Reactant: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Ni]
Solvent: CO
Product: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[(1S,3S)-3-(5-fluoro-2-nitro-phenoxy)-cyclopentyl]-acetamide (1.45 g) and Raney Ni (200 mg) in MeOH (150 ml) was stirred at rt overnight under hydrogen atmosphere (5 bar). The catalyst was removed by filtration and the filtrate was concentrated to give the desired product.