Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[N:23]=[C:22]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:15]=2)[CH2:21][C:22]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
5-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (1.0 g, 1.8 mmol) prepared in Example 116 and trifluoroacetic acid (1.4 mL, 18.0 mmol) were added at 0° C. to dichloromethane (9.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 1.1 g of the titled compound as a yellow liquid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:21][CH2:20][CH2:19][C@:15]45[C:16]=2[C:17]=1[O:18][C@H:14]4[C:13](=[O:22])[CH2:12][C@@H:11]([CH3:23])[C@@:10]35[O:24][CH3:25].[CH:26]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:26]1([CH2:30][N:21]2[CH2:20][CH2:19][C@:15]34[C:16]5[C:17]6[O:18][C@H:14]3[C:13](=[O:22])[CH2:12][C@@H:11]([CH3:23])[C@@:10]4([O:24][CH3:25])[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:3][CH3:2])[CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)NCC[C@]314
Reactant: BrCC1CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)N(CC2CCC2)CC[C@]314

Procedure:
A mixture of 3,14-dimethoxy-4,5α-epoxy-8α-methylmorphinan-6-one hydrochloride (4) (3.4 g, 9.29 mmol), cyclobutylmethyl bromide (3.4 g, 22.8 mmol), sodium bicarbonate (5.0 g, 59.5 mmol) and 100 milliliters of dimethylformamide was heated at 105° to 100° C. while being stirred and maintained under a nitrogen atmosphere. The reaction mixture was heated for 18 hours, after which the inorganic material was removed by filtration and the filter cake was washed twice with dimethylformamide (100 ml). The filtrate and washings were combined and distilled under high vacuum (bath temperatures 35° C.) and the material which remained was taken up with ethyl acetate (300 ml)/H2O (80 ml) and made basic by the addition of saturated sodium bicarbonate solution. After separating the organic layer, the aqueous phase was re-extracted with ethyl acetate (2×150 ml). The combined ethyl acetate extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 3.1 g (84% theory) of the crude desired product. This material was purified by chromatography on silica gel using benzene followed by 50:50 benzene/chloroform, chloroform and graded (2% to 50%) methanol/chloroform mixtures. Those fractions containing pure product were combined and evaporated to give 1.39 g (38% theory) of the desired compound as a foamy solid. A portion of the product was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN1CCCC1=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:13][CH:14]=1
Reactant: COc1ccc(I)cc1
Reactant: O=C(O)c1ccccc1S
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Sc2ccccc2C(=O)O)cc1
Temperature: 165 °C

Procedure:
First, 2-(4-methoxyphenylthio)benzoic acid was prepared. A stirred mixture of thiosalicylic acid (10.0 g, 65 mmol), 4-iodoanisole (15.18 g, 65 mmol), potassium carbonate (19.72 g, 143 mmol), copper powder (0.82 g, 13 mmol), and N-methylpyrrolidinone (100 mL) was deaerated by sparging with nitrogen for 10 min, heated at 165° C. for 18 h, and then cooled to ambient. The reaction mixture was poured onto a mixture of 500 g of ice plus 40 mL or concentrated HCl. The resulting precipitate was collected, washed with water, and dried. The product was purified by recrystallization from a mixture of water, ethanol, and tetrahydrofuran. A white powder was obtained, mass: 12.06 g (71% of theory).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][C:16]1([C:19]2[O:20][C:21]([CH:24]3[CH2:30][CH2:29][C@@H:28]4[CH2:31][N:25]3[C:26](=[O:40])[N:27]4[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:22][N:23]=2)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][C:16]1([C:19]2[O:20][C:21]([CH:24]3[CH2:30][CH2:29][C@@H:28]4[CH2:31][N:25]3[C:26](=[O:40])[N:27]4[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:22][N:23]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
TFA (30 mL) was added to a 0° C. solution of tert-butyl(1-(5-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)methylcarbamate (8 g, 0.017 mol) in DCM (100 mL). The mixture was allowed to warm to rt and was stirred at rt for 1 h. The mixture was concentrated and the residue was washed with Et2O (50 mL), and then filtrated to afford (5R)-2-(5-(1-(aminomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (7 g, 99%), which was used directly in the next step. ESI-MS (EI+, m/z): 370.2 [M+H]+.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20]([CH3:28])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[CH2:26]([O:25][C:23]([C:20]1([CH3:28])[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1(C)CCN(c2ccc(C(=O)OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ccc(C(=O)O)cc2)CC1

Procedure:
A mixture of Example 532E (0.54 g, 1.4 mmol) in ethanol (6 mL) at room temperature was hydrogenated at 60 psi over 10% Pd/C (58 mg) for 1.5 hours, filtered, and concentrated to provide the desired product. MS (DCI) m/e 292 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[C:11]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:10][N:9]=[C:8]3[C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:7]=[N:6][CH:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Cl
Reactant: Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-8-phenyl-N-(pyridin-2-ylmethyl) phthalazin-1-amine (50.0 mg, 0.124 mmol) in dichloromethane (5 mL) at ambient temperature was added pyridine (0.0200 mL, 0.247 mmol) followed by acetyl chloride (0.0132 mL, 0.185 mmol). After stirring for 5 h at room temperature, the reaction mixture was diluted with dichloromethane (50 mL) and the organic portion washed with water (10 mL) followed by brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 31 as described in general methods) to obtain N-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridin-3-yl)acetamide (25.0 mg, 45.3%) as a white solid. LCMS (Condition 4): retention time 2.08 min, [M+1]=447.2. HPLC (Condition 28): retention time=5.63 min, purity 94.65%. 1H NMR (400 MHz, CD3OD) δ 2.21 (s, 3 H), 4.65 (s, 2 H), 7.21-7.26 (m, 2 H), 7.49 (br s, 5 H), 7.69-7.73 (m, 2 H), 7.88-7.94 (m, 2 H), 8.28-8.30 (m, 1 H), 8.42 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 8.55 (d, J=2.0 Hz, 1 H), 8.90 (d, J=2.4 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH:23][C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:22].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[CH3:22][CH2:21][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([C:18]([C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[CH:12]=2)=[O:20])[CH2:32][CH2:31]1
Reactant: CCNc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCNc1cccnc1N1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with 5-benzyloxyindole-2-carboxylic acid (1.0 g), 1-(3-ethylamino-2-pyridinyl)piperazine (International Publication WO 87/01706, 0.81 g), 1,1'-carbonyldiimidazole (0.61 g) and THF (7 ml), the title compound is obtained, mp 192°-193°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14](=O)[C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=2[CH2:26][CH2:27][CH3:28])=[C:7]([O:9][N:10]=C(C)C)[CH:8]=1>C(#N)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]([C:15]3[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[CH2:26][CH2:27][CH3:28])=[N:10][O:9][C:7]=2[CH:8]=1
Reactant: CCCc1cc(C(=O)c2ccc(OC)cc2ON=C(C)C)c(CCC)cc1OC
Agent: Cl
Solvent: CC#N
Product: CCCc1cc(-c2noc3cc(OC)ccc23)c(CCC)cc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
A red mixture of acetone O-[5-methoxy-2-(4-methoxy-2,5-dipropylbenzoyl)phenyl]oxime (2.30 g, 5.79 mmol) in acetonitrile (43 mL) and 5% aqueous HCl (32 mL) was stirred at 80° C. for 4 h. Most of the acetonitrile was removed in vacuo and extraction was conducted in CH2Cl2 (3×60 mL) with 33% saturated brine (50 mL). Flash chromatography with silica gel (gradient to 8% EtOAc/hexanes) provided the title compound as a colorless oil (1.72 g, 87% yield for two steps): 1H NMR (300 MHz, CDCl3) δ 0.84 (t, 3H, J=7.3 Hz), 0.96 (t, 3H, J=7.4 Hz), 1.58 (m, 4H), 2.60 (t, 2H, J=7.6 Hz), 2.70 (t, 2H, J=7.8 Hz), 3.89 (s, 3H), 3.92 (s, 3H), 6.84 (s, 1H), 6.92 (dd, 1H, J=8.7, 2.1 Hz), 7.05 (d, 1H, J=2.0 Hz), 7.23 (s, 1H), 7.40 (d, 1H, J=8.7 Hz); MS m/e 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)=[O:15])[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)O)C1
Reactant: CC1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCN(C(=O)CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
A mixture of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoic acid (50 mg, 0.17 mmol), 4-methyl Piperidine (0.02 mL, 0.17 mmol), DCC (38 mg, 0.18 mmol), and DMAP (23 mg, 0.18 mmol) in dry DCM (2 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated to obtain 12 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)propan-1-one as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C@@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:13][OH:14])[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[N:26][N:27]([CH3:38])[C:28]=1B1OC(C)(C)C(C)(C)O1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:23][C:24]1[CH:25]=[N:26][N:27]([CH3:38])[C:28]=1[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C@@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:13][OH:14])[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccc(Br)nc2CN1[C@H](CO)Cc1cccc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@H](CO)Cc1cccc(F)c1)C2=O
Yield: 70.3 %

Procedure:
In one 20 mL vial, a mixture of 2-bromo-6-[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (0.041 g, 0.11 mmol), 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0327 g, 0.135 mmol), bis(tri-t-butylphosphine)palladium (0.00574 g, 0.0112 mmol), and N,N-diisopropylethylamine (0.0587 mL, 0.337 mmol) in 1,4-dioxane (5 mL) was microwaved at 120° C. for 20 minutes. The resulting mixture was filtered through a pad of celite and concentrated, and the residue was purified by combi-flash chromatography using hexane/EtOAc/methanol to give 31 mg (68% yield) of the final product. LC/MS found: 401.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:27]5[N:26]([CH3:25])[CH:30]=[CH:29][CH:28]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cn1cccc1C(=O)Cl
Solvent: CC(=O)N(C)C
Product: Cn1cccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 61.7 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol), 1-methyl-1H-pyrrole-2-carbonyl chloride (151 mg, 1.05 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 148, the title compound (268 mg, 62%) was obtained as colorless crystals.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(C(F)(F)F)c1
Reactant: C1CCNCC1
Product: FC(F)(F)c1cc(CN2CCCCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 63 and piperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]([OH:15])=O)[N:8]=[CH:7][CH:6]=[CH:5]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]=[CH:6][CH:7]=[N:8]3)=[CH:3][C:2]=2[F:1])[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cc2ncccc2cc1F
Product: O=C(Cc1cc2ncccc2cc1F)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-7-yl)acetamide was prepared from 2-(6-fluoroquinolin-7-yl)acetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=2.338, method [7], MS(ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.02 (d, J=4.2 Hz, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7.88 (d, J=10.0 Hz, 1H), 7.82 (dd, J=9.0, 4.2 Hz, 1H), 7.09 (s, 1H), 4.42 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].O(CC)[C:11]([S-])=[S:12].[K+].Cl>N1C=CC=CC=1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:11](=[S:12])[O:8][C:7]=2[CH:6]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1ccc(N)c(O)c1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-amino-m-cresol (593.7 mg, 4.82 mmol) and potassium O-ethyl xanthate (850 mg, 5.30 mmol) in pyridine (10 mL) was stirred and heated to reflux for 2 h. It was cooled to rt, poured into a mixture of ice-water (40 mL), and concentrated HCl (4 mL). The solid was collected, washed with water, and dried in the hood overnight and then in a vacuum oven at 45° C. for 3 h. The product 6-methyl-1,3-benzoxazole-2(3H)-thione was obtained as beige powder (735 mg, yield 92.3%). 1H NMR (300 MHz, DMSO-d6) δ 7.10 (s, 1 H), 7.03 (d, 2 H), 2.42 (s, 3 H); LC-MS ret. time 2.37 min (method 2), m/z 166.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:15][CH2:16]O>>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1])[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-nitrobenzoic acid (0.85 g, 4.22 mmol) in anhydrous EtOH (50 mL) was bubbled with dry hydrogen chloride for 2 h at room temperature and the mixture was then stirred at room temperate overnight. After evaporation of solvent, water (100 mL) was added and the precipitates were collected by filtration and dried to give 2-chloro-3-nitro-benzoic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1>C(#N)C.C(OC(=O)C)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: C[C@@H](N)CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H](CO)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 315 mg (4.2 mmol) of (R)-2-Amino-propan-1-ol in 5 ml of acetonitrile is added slowly to a suspension of 388 mg (2.0 mmol) of 2,4-dichloro-5-nitro-pyrimidine in 20 ml acetonitrile at −30° C. to −20° C. The batch is stirred for 3 hours at −30° C. to −20° C. The batch is diluted with ethylacetate and ice water. The batch is extracted with ethyl acetate (3×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. 350 mg (1.51 mmol, corresponding to 76% of theory) of the product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[CH:16][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=CCc1cccc(Br)c1
Reaction time: 16 h

Procedure:
60 g (246 mmol) of ethyl (3-bromophenyl)acetate (Compound B1) was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutyl aluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxy methylene)triphenylphosphorane and 1.7 g of 10% Pd/C. The procedure was as follows: To a cold solution (−78° C.) of Compound B1 in CH2Cl2 was added dropwise (over a span of 1 hour) the diisobutyl aluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at −78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol, followed by water and 10% HCl. The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water, 10% aqueous NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (3-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in CH2Cl2 was added a solution of the (carbethoxy methylene)triphenylphosphorane reagent in CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(3-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in EtOAc and hydrogenated over 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid. PMR (CDCl3): δ1.26 (3H, t, J=7.1 Hz), 1.89-2.00 (2H, m), 2.31 (2H, t, J=7.5 Hz), 2.63 (2H, t, J=7.2 Hz), 4.15 (2H, q, J=7.1 Hz), 7.10-7.35 (4H, m).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[N:15]1([CH2:24][C:25]2[CH:26]=[C:27]3[C:33]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:15]1([CH2:24][C:25]2[CH:26]=[C:27]3[C:33]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: Cn1cc(-c2c[nH]c3ncc(CN4CCc5ccccc54)cc23)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(-c2c[nH]c3ncc(Cn4ccc5ccccc54)cc23)cn1
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (25 mg, 0.11 mmol) was added in small portions over a period of 0.5 h to a stirred solution of 59 (11.0 mg, 33.4 μmol) in CH2Cl2 (1.8 mL)-0.2 M aqueous phosphate buffer (pH 7.0) solution (0.05 mL). When the addition was completed, the mixture was stirred for additional 0.5 h and then treated with saturated aqueous NaHCO3 (2 mL). Stirring continued for 1 h. The organic layer was separated and the aqueous phase extracted with CH2Cl2 (5×2 mL). Combined organic solutions were washed with brine, dried (MgSO4), concentrated and the residue was purified by means of PTLC using AcOEt as eluent to afford 60 (2.9 mg, 26%) as grey solid; 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 5.46 (s, 2H), 6.56 (dd, J=3.2, 0.7 Hz, 1H), 7.12 (td, J=7.5, 1.0 Hz, 1H), 7.16 (d, J=3.2, 1H), 7.20 (td, J=7.5, 1.2 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.39 (dd, J=8.2, 0.7 Hz, 1H), 7.47 (s, 1H), 7.66 (s, 1H), 7.66 (dd, J=7.8, 0.7 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.86 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C)cc2SC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)S2
Temperature: 25 °C
Reaction time: 4.8 h
Yield: 10.8 %

Procedure:
The ester from Step 3 (2.02 g, 6.0 mmol) was dissolved in THF (10 mL) and ethanol (10 mL), treated with 2.5 N sodium hydroxide (5.5 mL, 13.8 mmol), and stirred at room temperature for 4.8 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl yielding a suspension. The solid was collected by filtration and was recrystallized from ethanol-water to yield the title compound as a yellow solid (0.20 g, 11%): mp 240.5–241.7° C. 1H NMR (acetone-d6/300 MHz) 7.99 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 4.99 (q, 1H, J=8.5 Hz), 2.39 (s, 3H). FABLRMS m/z 307 (M−H). FABHRMS m/z 306.9831 (M−H, Calc'd 306.9807). Anal. Calc'd for C12H8ClF3O2S: C, 46.69; H, 2.61; Cl, 11.48. Found: C, 46.78; H, 2.61; Cl, 11.41.