Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pivaloyl chloride (96 g) in methylene chloride (200 ml) is added dropwise to a cooled mixture of 2-aminopyridine (50 g) and triethylamine (108 g) in methylene chloride (650 ml). The reaction mixture is stirred overnight at RT and poured into water which is basified and the organic layer separated and concentrated in vacuo. Hexane is added to the oil which results in the precipitation of a crystalline solid which is filtered and the solid taken up in aqueous acid. The desired pyridine compound is recrystallized as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1.[BH4-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2c(Cl)cccc2Cl)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: OCc1csc(-c2c(Cl)cccc2Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
To a cooled (0° C.) solution of ethyl 2-(2,6-dichlorophenyl)thiazole-4-carboxylate (7.0 g, 23 mmol) in MeOH (100 mL) was added lithium borohydride (0.98 g, 47 mmol) in four portions. After addition, the mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography eluting with EtOAc/petroleum ether (1:5) to give the desired product as a white solid (6.2 g, 97% yield). 1H NMR (DMSO-d6, 500 MHz): δ 7.74 (s, 1H), 7.66-7.64 (m, 2H), 7.60-7.56 (m, 1H), 5.52 (t, J=5.5 Hz, 1H), 4.70 (m, 2H). LCMS (ESI) m/z: 260.1 [M+H+].
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:55])[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1>O1CCOCC1.Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:55])[CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Cc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 18 h
Yield: 48 %

Procedure:
Hydrolysis was performed by stirring N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)2-phenylacetamide (0.186 g, 0.207 mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 18 hours. The title compound was purified by preparative HPLC (0.039 g, 48% yield): 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.2 (s, 1H), 8.1 (dd, 1H), 7.7–7.6 (m, 3H), 7.5 (t, 1H), 7.4–7.2 (m, 4H); ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[CH:5][CH2:6][C:7]([F:10])([F:9])[F:8]>C(O)C>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8]
Reactant: COC(=O)C(=CCC(F)(F)F)NC(=O)OCc1ccccc1
Solvent: CCO
Product: COC(=O)[C@H](CCC(F)(F)F)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Benzyloxycarbonylamino-5,5,5-trifluoropent-2-enoic acid methylester (15.37 g, 48.5 mmol) was dissolved in absolute ethanol (100 mL) in a Parr hydrogenation vessel. The solution was sparged with a stream of nitrogen and then (+)Duphos (350 mg) was added. The reaction mixture was placed on a Parr hydrogenation apparatus and the headspace was evacuated and then pressurized with 50 psi of hydrogen. This process was repeated seven times and the vessel was then pressurized with 50 psi of hydrogen and agitated on the Parr apparatus overnight. The reaction mixture was then concentrated by rotary evaporation, dissolved in 1:1 ethyl acetate:hexanes, and filtered through a bed of silica to remove catalyst. The filtrate was concentrated by rotary evaporation yielding crude (S)-2-benzyloxycarbonylamino-5,5,5-trifluoropentanoic acid methyl ester that was carried forward without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:7]=[CH:8][CH:9]=1.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[NH:23][N:22]=[C:21]2[Cl:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(N(C)C)=O>[Cl:29][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([NH:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH3:16])[CH:5]=3)[CH:19]=2)[C:24](=[O:28])[NH:23][N:22]=1
Reactant: CN(C)CCCNc1cccc(CN)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCCNc1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Temperature: 85 °C
Yield: 17.3 %

Procedure:
A mixture of N-(3-aminomethyl-phenyl)-N′,N′-dimethyl-propane-1,3-diamine hydrochloride (65 mg, 0.267 mmol), 6-bromo-4-chloro-2H-phthalazin-1-one (66 mg, 0.254), Pd2(dba)3 (31 mg, 0.0339 mmol), rac-BINAP (57 mg, 0.0915 mmol), NaOtBu (88 mg, 0.916 mmol) and DMA (5 mL) was heated to 85° C. until the reaction was completed by HPLC. The reaction was filtered through celite and purified by preparatory HPLC to yield 4-chloro-6-[3-(3-dimethylamino-propylamino)-benzylamino]-2H-phthalazin-1-one hydroformate (17 mg) as an orange solid. 1H (400 MHz, d6-DMSO) δ: 1.62 (quintet, 2H), 2.11 (s, 6H), 2.26 (t, 2H), 2.98 (t, 2H), 4.29 (d, 2H), 6.42 (d, 1H), 6.53 (m, 2H), 6.81 (s, 1H), 7.10 (t, 1H), 7.12 (dd, 1H), 7.60 (t, 1H), 7.91 (d, 1H), 8.20 (s, 2H), 12.32 (s, 1H) ppm; m/z (M+1) 385.96.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl.C(OCC)C>[CH2:1]([C:8]1[CH:13]=[C:12]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccnc(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCN(c2ccnc(Cc3ccccc3)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-benzyl-4-chloropyridine (0.480 q; see Example 1) and N-methylpiperazine (1.0 ml) is heated at 125° under an inert atmosphere for 17 hours. Upon cooling to room temperature, the mixture produces a crystalline mass. The crude solid is treated with saturated aqueous potassium carbonate (5 ml), water (2 ml), diethyl ether (5 ml) and dichloromethane (5 ml). The organic layer is separated, dried and concentrated to an oil. Excess N-methylpiperazine is removed by drying the oil at 45° under high vacuum (10 torr), giving the title compound as a viscous oil. Structure assignment is confirmed by nmr spectroscopy. nmr (CDCl3): δ (ppm) 2.34 (s, 3H); 2.48 (dd, 4H); 3.28 (dd, 4H); 4.07 (s, 2H); 6.5 (m, 3H); 7.26 (m, 4H); 8.22 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][O:17][CH2:18][C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)=[O:20].N1CCCCC1.O>C(Cl)(Cl)Cl>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([NH:21][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH:23]=1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Reactant: COCC(=O)Nc1cccc(C=O)c1
Solvent: C1CCNCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COCC(=O)Nc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
In 3 ml of chloroform were dissolved 0.18 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 0.17 g of 3-(methoxyacetylamino)benzaldehyde and 60 mg of piperidine, and the solution was heated under refluxing for 1 hour and 10 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and fractions corresponding to Rf=0.3 were collected by thin layer chromatography (silica gel, chloroform (containing 2% methanol)), and concentrated to obtain 0.30 g of 4-hydroxy-3-[3-[3-(methoxyacetylamino)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (21d)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:18])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:52]1([CH2:57][C@H:58]2[NH:61][C:60](=[O:62])[C@H:59]2[NH2:63])[CH:56]=[N:55][CH:54]=[N:53]1>C(Cl)Cl.CN(C=O)C.CN(C=O)C>[N:52]1([CH2:57][C@@H:58]2[C@H:59]([NH:63][C:15](=[O:17])[C:14]([C:12]3[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[S:10][CH:11]=3)=[O:18])[C:60](=[O:62])[NH:61]2)[CH:56]=[N:55][CH:54]=[N:53]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)cs1
Reaction time: 48 h
Yield: 67.8 %

Procedure:
To a slurry of 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (2.72 g, 9.99 mmol) and HATU (3.80, 10.0 mmol) in DCM:DMF (3:1, 33.3 mL) at 0° C. was added DIPEA (2.91 mL, 16.7 mmol). A soln of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (1.39 g, 8.33 mmol) in DCM:DMF (1:1, 32 mL) was added followed by a DMF (3 mL) wash. After stirring for 48 h the dark solution was diluted with EtOAc (150 mL)/brine (140 mL) and the layers were separated. The aqueous was extracted with EtOAc (3×) and the combined organic layers were washed with brine (70 mL). The brine layer wash was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concd in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%), affording the title compound (2.38 g, 68%) as a red solid. LCMS: Rt=0.59 min, m/z=422.0 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.70 (d, J=9.3 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 5.28 (ddd, J=9.3, 5.2, 1.5 Hz, 1H), 4.45 (dd, J=14.2, 5.3 Hz, 1H), 4.36 (dd, J=14.1, 7.6 Hz, 1H), 4.18 (dt, J=7.6, 5.3 Hz, 1H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[N:7]([CH:27]1[CH2:30][N:29](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:28]1)[CH2:8][C@H:9]([OH:26])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6](=[O:44])[N:7]([CH:27]1[CH2:30][NH:29][CH2:28]1)[CH2:8][C@H:9]([OH:26])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccc(OCc2ccccc2)cc1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccc(O)cc1)C1CNC1
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a solution of (1-Benzhydryl-azetidin-3-yl)-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.55 g, 0.9 mmol) in methanol (20 ml) was added ammonium formate (2.0 g, 30 mmol), and 0.2 g of 10% Pd/C. The mixture was stirred at reflux for 18 h. After cooling to room temperature, it was filtered through Celite. The solvent was evaporated to give 0.31 g of a beige solid; m.p. 130-134° C.; MS (ES) m/z 339.1 (MH+); HRMS (El) Calcd. for C37H42N2O5 (M+): 338.1841, Found: 338.1833.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.[CH:32](=O)[CH2:33][CH2:34][CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[N:3]1([C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][C:14]=3[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:23])=[O:11])[CH2:6][CH2:5]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=CCCCC=O
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](N2CCCCC2)CC1

Procedure:
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (125 mg) obtained in Example 219 is suspended in dichloromethane (10 ml), and thereto is added triethylamine (102 μl) under ice-cooling, and the mixture is stirred for several minutes. Then, about 25% aqueous glutaraldehyde solution (150 mg) and sodium triacetoxy borohydride (155 mg) are added successively, and the mixture is stirred under ice-cooling for 2 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed successively with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, then 1/1) to give trans-3-[4-(piperidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (106 mg). Subsequently, this product is dissolved in chloroform/methanol (5/1, 6 ml), and 4N hydrogen chloride in ethyl acetate (5 ml) is added thereto under ice-cooling. The reaction solution is concentrated under reduced pressure, and the resulting residue is suspended in diethyl ether, and collected by filtration to give the title compound (107 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[S:8][C:7]=12.[CH3:24][C@H:25]1[CH2:30][O:29][CH2:28][CH2:27][NH:26]1>CN1C(=O)CCC1.O>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([C:9]3[S:8][C:7]4=[C:2]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][C@@H:25]5[CH3:24])[N:3]=[N:4][CH:5]=[C:6]4[CH:10]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Reactant: C[C@H]1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(N3CCOC[C@@H]3C)c2s1
Temperature: 165 °C

Procedure:
A mixture of 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide (90 mg, 262 μmol) and (S)-3-methylmorpholine (79 mg, 785 μmol) in NMP (2 ml) was heated to 165° C. for 48 hrs. The mixture was cooled to RT, diluted with H2O and filtered. The solids were washed with H2O and air-dried. The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to afford the title compound. MS (ESI, pos. ion) m/z: 409 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-])=O>CC(O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+].[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH2:12]
Reactant: O=[N+]([O-])c1cc(F)c(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc([N+](=O)[O-])cc(F)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
A mixture of 2-bromo-1,5-dinitro-3-fluorobenzene (100 mg, 0.38 mmol, 1 equiv) and iron powder (64 mg, 1.14 mmol, 3 equiv) in 3 mL of HOAc was stirred at room temperature for 90 minutes. The reaction mixture was diluted with EtOAc (20 mL) and saturated NaHCO3 (to ca. pH 7-8). The organic layer was separated and evaporated under vacuum. The crude residue was purified by column chromatography on silica gel using EtOAc/hexanes (1:4) as eluent to give 47 mg of 2-bromo-3-fluoro-5-nitroaniline (52%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:12]([O-])=O.[Na+]>Cl.O>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4]([NH2:12])=[N:5][NH:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C#N)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(N)n[nH]c2c1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
To an ice-cooled suspension of 66.35 g (0.448 mol) of 2-amino-4-methoxybenzonitrile in 530 ml of concentrated HCl, a solution of 37.07 g (0.537 mol) of sodium nitrite in 55 ml of water was added dropwise. After 1.5 hours the cold suspension was added dropwise to a preformed solution of 679.25 g (3.58 mol) of stannous chloride in 530 ml of concentrated hydrochloric acid (HCl), at SOC. After 3 hours the cold suspension was filtered and the moist solid was treated with 1.7 l of boiling water for 30 min. The hot cloudy solution was clarified by filtration through a cloth filter. The liquors were ice-cooled and treated dropwise with 0.8 l of 17% NaOH. The solid was filtered off and dried under vacuum at 50° C.: 67.2 g of product were obtained as light brown solid. Yield=91.9%. mp=195-197° C. dec. HPLC r.t. 1.9 [M+H]+=164
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:14][C@H:13]3[N:15]([CH3:16])[C@H:10]([CH2:11][CH2:12]3)[C@@H:9]2[C:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)C.O1CCCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:18][C:17]([C@@H:9]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:14][C@H:13]3[N:15]([CH3:16])[C@@H:10]2[CH2:11][CH2:12]3)=[O:19])=[CH:27][CH:26]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CN1[C@H]2CC[C@@H]1[C@H](C(=O)[O-])[C@@H](c1ccc(F)cc1)C2
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1[C@H]2CC[C@@H]1[C@H](C(=O)Oc1ccc(Cl)cc1)[C@@H](c1ccc(F)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of (1R,2R,3S)-3-(4-fluorophenyl)tropane 2-carboxylate (1.4 g, 5 mmol) and thionyl chloride (5 ml) was refluxed for one hour and the reaction mixture was concentrated in vacuo. The remanescens was suspended in diethyl ether (20 ml) and a solution of 4-chlorophenol (0.64 g, 5 mmol) and triethyl amine (1.4 ml, 10 mmol) in diethyl ether (10 ml) was added at room temperature. The mixture was stirred at room temperature over night and tetrahydrofurane (30 ml) was added and the mixture was refluxed for three hours. The reaction was quenched by addition of water (50 ml) and was extracted with diethyl ether. The combined organic phase was washed with sodium hydroxide (1M) and three times with water. After drying and concentration in vacuo the crude product was subjected to column chromatography first with ethyl acetate and later with ethyl acetate and methanol (20%) as eluent yielding the title compound as white crystals, m.p. 64°-66° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].[CH:23]([C:25]([CH3:27])=O)=[CH2:24]>P(=O)(O)(O)O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[O:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:5]([N+:2]([O-:4])=[O:3])=[C:6]2[C:8]=1[C:25]([CH3:27])=[CH:23][CH:24]=[N:7]2
Reactant: C=CC(C)=O
Reactant: COc1cc([N+](=O)[O-])c(N)cc1Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=P(O)(O)O
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
A mixture of 83 g of 2-nitro-4-methoxy-5-(3,4-dichlorophenoxy)aniline hydrochloride (0.22 mole) polyphosphoric acid in 250 ml of 85% phosphoric acid was heated in a nitrogen atmosphere at 110-120° C. and 32.17 g of methyl vinyl ketone (0.46 mole) was added dropwise under vigorous stirring. After the addition was complete, the mixture was stirred and maintained at 110-120° C. for a further 4 hours. An additional 14 g of methyl vinyl ketone (0.2 mole) was added and the mixture was heated for a further 4 hours. The reaction mixture was poured into ice cold sodium hydroxide solution (pH 10-12) and left over night. The resulting precipitate was separated by filtration and dried. The solid was dissolved in chloroform and mixed with activated charcoal and filtered through a celite bed. The celite bed was washed with chloroform and the filtrate was concentrated to 400 ml under vacuum and diluted with methanol until a turbidity appeared and left overnight. The crystalline product formed was separated by decantation and crystallized from chloroform to give 8 g of pure product, 5-(3,4-dichlorophenoxy)-6-methoxy-4-methyl-8-nitroquinoline. The combined filtrates were evaporated to dryness and the residue was chromatographed over silica gel with 30% chloroform in hexane to yield a fraction from which the product which was crystallized (chloroform/methanol) to give 13 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([S:8]([OH:11])(=[O:10])=[O:9])[CH:7]=1.[Na].[OH-].[Na+].[CH2:16]1[O:24][CH:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][OH:24])=[C:6]([S:8]([OH:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: O=S(=O)(O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1cc(Cl)ccc1OC(CO)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-hydroxybenzenesulfonic acid, sodium salt (7.9 g), NaOH (1.37 g) and water (25 ml) was heated on a boiling water bath until the mixture became homogeneous. Styreneoxide (2.4 g) was added dropwise over a period of 10 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. It was extracted with ether and the aqueous solution was evaporated to dryness. The residue was treated with water and the insoluble white precipitate was collected by filtration and washed with 5 mL water to obtain 2-(4-chloro-2-sulfophenoxy)-2-phenylethanol (4.1 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1>ClCCl>[CH3:5][C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:3])=[O:16])=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Thionyl chloride (2.00 mL) is added to 4-(4-methyl-oxazol-5-yl)-benzoic acid (400 mg) in dichloromethane (5 mL) and the mixture is stirred for two days at room temperature. The solvent is evaporated to give the title compound, which is used without further purification for the next reaction step.