Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH2:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][CH2:27]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:27][CH2:26][CH2:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=2)[NH:21][CH:20]=1
Reactant: COc1ccc2[nH]cc(CCCBr)c2c1
Reactant: NCC1COc2ccccc2O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCNCC3COc4ccccc4O3)c2c1
Temperature: 80 °C
Yield: 33.6 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.3 g, 11.0 mmole) in DMF (100 ml) was slowly added to a mixture of 5-methoxy-3-(3-bromopropyl)indole (3.0 g, 11.0 mmole) and diisopropylethylamine (9.7 ml, 55 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed in vacuum and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (1.3 g, 3.7 mmole, 34%) were concentrated, treated with 0.25M of fumaric acid in ethanol (8.1 ml, 2.0 mmole) and diluted first with 50 ml of ethanol-diethyl ether (1:1) and then with a minimum amount of hexane to precipitate the title compound as a white solid, (2:1) fumarate salt, m.p. 135°-136° C.
Reaction SMILES: [CH:1]([CH2:3][C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[CH2:13](O)[CH2:14][OH:15].O>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:7][CH:6]1[CH2:5][C:4]([CH3:11])([CH3:12])[CH2:3][C:1]([O:15][CH2:14][CH3:13])=[O:2]
Reactant: OCCO
Reactant: CCOC(=O)CC(C)(C)CC=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(C)CC1OCCO1
Yield: 93.3 %

Procedure:
74 g of ethyl 4-formyl-3,3-dimethylbutanoate, prepared in Example 91, are dissolved in 450 ml of anhydrous toluene in the presence of 0.5 g of paratoluenesulfonic acid and 26.7 g of ethylene glycol. The mixture is heated to the reflux temperature and the water formed during the reaction is removed by means of a Dean-Stark apparatus. After refluxing for two hours, the solvent is evaporated off under vacuum and the residue is distilled to give 86.7 g of ethyl 4-(dioxolan-2-yl)-3,3-dimethylbutanoate in the form of a liquid with a boiling point b.p. of 138°-140° C.
Reaction SMILES: [H-].[Na+].[C:3]([OH:8])#[C:4][CH2:5][CH2:6][CH3:7].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>C1COCC1>[CH2:3]([O:8][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:5][C:6]#[CH:7]
Reactant: CCCC#CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCOCc1ccccc1
Temperature: 0 °C
Yield: 94.5 %

Procedure:
To a flame-dried round-bottomed flask was added NaH (2 equiv., 47.6 mmol, 1.9 g of a 60% dispersion in mineral oil). The solid was washed with hexanes (15 mL), THF (95 mL) was added and the suspension was cooled to 0° C. Pentynol (1 equiv., 23.8 mmol, 2.0 g) was added drop wise in THF (5 mL), followed by drop wise addition of BnBr (0.92 equiv., 21.9 mmol, 2.60 mL). The reaction was warmed to ambient temperature over 16 h, quenched with saturated aqueous NH4Cl (25 mL), and diluted with water (20 mL). The organic layer was extracted with EtOAc (2×40 mL), washed with brine (40 mL) and dried with Na2SO4. Product isolation was achieved by concentration in vacuo and purification by flash column chromatography to afford ((pent-4-yn-1-yloxy)methyl)benzene (3.60 g, 20.7 mmol, 94%). TLC Rf=0.41 (5% EtOAc/Hex); 1HNMR (300 MHz): δ 7.29-7.44 (5H), 4.55 (s, 2H), 3.61 (t, 2H, J=6.2 Hz), 2.36 (td, 2H, J=7.1, 2.6 Hz), 1.97 (t, 1H, J=2.6 Hz), 1.81-1.93 (m, 2H). 13CNMR (75 MHz): δ 138.5, 128.4, 127.63, 127.58, 84.0, 73.0, 68.7, 68.5, 28.7, 15.3.
Reaction SMILES: [N+:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred mixture of 6-nitro-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (81 mg, 0.295 mMol) in ethanol (3 mL) was added SnCl2.2H2O (331 mg, 1.47 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring to 0.5 h, to form a clear solution and continually refluxed for another 0.5 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL) to give 70 mg (97%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 32 mg of pure title compound as bright yellow needles; mp: 342°-5° C. (dec. from 335° C.), changed color from 325° C. IR (KBr, cm-1): 3468, 3362, 3193, 1693, 1631, 1493, 1375; NMR (1H, DMSO-d6): δ 5.418 (s, 2H); 6.999 (s, 1H); 11.238 (s, 1H); 11.776 (s, 1H). HRMS: calcd for C8H5N3O2Cl2 (M+) m/z: 244.9757; found 244.9769. Potency relative to DCK: 8.6%.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)C=O)[CH3:2].C([C:14](=[O:18])[C:15]([O-:17])=[O:16])C.[OH-].[Na+]>C(O)C>[O:18]=[C:14](/[CH:2]=[CH:1]/[C:3]1[CH:10]=[CH:9][CH:8]=[CH:5][C:4]=1[F:11])[C:15]([OH:17])=[O:16]
Reactant: CCC(=O)C(=O)[O-]
Reactant: CCc1cccc(C=O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)/C=C/c1ccccc1F
Reaction time: 0.75 h
Yield: 57.2 %

Procedure:
To a magnetically stirred solution of ethyl 2-fluorobenzaldehyde (11.7 ml, 110 mmol) and ethylglyoxalate (11.1 ml, 100 mmol) in ethanol (50 ml) was slowly added a solution of sodium hydroxide (4.4 g (110 mmol) in 50 ml water) in a nitrogen atmosphere while the temperature was kept between 0° C. and 10° C. After stirring for another 45 minutes the reaction mixture was allowed to attain room temperature and stirred for 2 hours. The formed precipitate was collected by filtration and successively washed with ethanol and a 1N HCl solution (200 ml) and subsequently dried to give E-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid (11.1 gram, 57% yield) Melting point: 100-102.5° C. 1H-NMR (400 MHz, CDCl3) δ 7.13-7.27 (m, 2H), 7.45-7.53 (m, 1H) 7.66-7.74 (m, 2H), 8.26 (d, J=16, 1H), invisible —OH proton.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]=[C:29]=[S:30])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:28][C:29](=[S:30])[NH:1][C:2]2[S:12][C:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=3[C:3]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:27])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: COc1ccc(C(=O)N=C=S)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)cc1
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A solution of tert-butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (1.0 mL, 0.083 M, 0.083 mmol) in THF was added to a solution of 4-methoxybenzoyl isothiocyanate (51 mg, 0.26 mmol) in THF (1 mL) and heated at 50° C. for 16 hours, then cooled to room temperature. The solvent was removed and EtOH (2 mL) was added. The product was filtered and rinsed with EtOH (3×5 mL). tert-Butyl 2-(3-(4-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (31 mg, 0.065 mmol, 78% yield) was isolated as a white solid. 1H NMR (400 MHz, CDCl3) δ 14.65 (s, 1H), 8.98 (s, 1H), 7.83 (apparent d, J=8.9 Hz, 2H), 6.91 (apparent d, J=8.9 Hz, 2H), 4.66 (s, 2H), 3.81 (s, 3H), 2.69 (s, 2H), 1.56 (s, 9H), 1.24 (s, 6H). 13C NMR (101 MHz, CDCl3) 173.90, 164.52, 164.49, 163.88, 147.40, 129.93, 129.13, 124.58, 123.65, 118.03, 114.34, 82.36, 70.79, 59.81, 55.62, 38.25, 28.49, 26.48.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[Na].[Cl:7][C:8]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>O>[Cl:7][C:8]1[CH:15]=[C:14]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: OCCCO
Agent: [Na]
Solvent: O
Product: N#Cc1ccc(OCCCO)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
To 1,3-propanediol (320 mg, 4.2 mmol) was added sodium (21 mg, 0.92 mmol). The mixture is stirred at room temperature for 10 minutes and 2-chloro-4-fluoro-benzonitrile (156 mg, 1.0 mmol) was added. The reaction was heated to 105° C. for 24 hours. The reaction was cooled to room temperature, was diluted with water and was extracted with Et2O (3×). The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified by reverse phase high pressure chromatography eluting with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) to provide 107 mg of 2-chloro-4-(3-hydroxy-propoxy)-benzonitrile. 1H NMR (CDCl3) δ 7.54 (d, 1H), 7.00 (m, 1H), 6.85 (dd, 1H), 4.15 (t, 2H), 3.83 (t, 2H), 2.04 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:24](OC)[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C>[CH2:12]([O:11][CH2:10][C@@H:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:24]=[CH:25][N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH:38]=[CH:37][N:36]=[CH:35]3)=[CH:32][CH:33]=2)[C:19]1=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(CNCc1ccc(-n2ccnc2)cc1)OC
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C=CN(Cc2ccc(-n3ccnc3)cc2)C(=O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of N-tert-butoxycarbonyl-O-benzyl-L-serine (1.48 g) and 2,2-dimethoxyethyl[4-(1H-imidazol-1-yl)benzyl]amine (1.31 g) in acetonitrile (50 ml) were added HOBt (842 mg) and WSC hydrochloride (1.05 g), under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the mixture was added N,N-dimethylaminopyridine (catalytic amount), and the mixture was stirred overnight. The reaction solution was concentrated, and to the residue were added ethyl acetate and water. The organic layer was separated, washed with saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate:methanol=20:1). To the obtained product were added p-toluene sulfonic acid (856 mg) and toluene (60 ml), and the mixture was refluxed for 30 minutes and cooled. To the reaction solution was added ethyl acetate, and the mixture was washed with saturated sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate:methanol=20:1) to give amorphous of the title compound (1.14 g).
Reaction SMILES: [N:1]1[C:2](=[O:12])[CH:3]=[CH:4][CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.[H-].[Na+].Cl[CH2:16][C:17]#[N:18].Cl>CN(C=O)C.CCOC(C)=O>[C:17]([CH2:16][N:1]1[C:2](=[O:12])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:18]
Reactant: O=c1cccc2ccccc2n1
Reactant: N#CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCN1C(=O)CCc2ccccc2C1c1ccccc1
Reaction time: 1 h
Yield: 190.5 %

Procedure:
To a solution of 1.80 g of the benzazepinone of Example 1 (7.6 mmol) in 15 mL of DMF was added 13 mg of KI (0.76 mmol, 0.01 eq.) and 200 mg of NaH (8.4 mmol, 1.1 eq.). After 1 hr at 25°, 0.58 mL of ClCH2CN (9.2 mmol, 1.2 eq.) was added, causing a dark red solution to form. After 24 hr an additional 200 mg of NaH (8.4 mmol, 1.1 eq.) and 0.58 mL of ClCH2CN (9.2 mmol, 1.2 eq.) were added. After a further 8 hr, 150 mL 0.5N of HCl was added, followed by 150 mL of EtOAc. The EtOAc layer was then washed with saturated NaCl (2×150 mL), dried (Na2SO4), and the solvents evaporated to yield 2.0 g of crude 2-cyanomethyl-1-phenyl-1,2,4,5-tetrahydro-2 (3H)benzazepin-3-one as a red oil. This oil was immediately dissolved in 60 mL of glacial HOAc, 0.5% of 10% Pd/C was added, and the resulting mixture was hydrogenated for 4 hr at 50 psi. An additional 0.5 g of 10% Pd/C was added and the mixture hydrogenated a further 4 hr at 50 psi. The reaction mixture was filtered through celite, the filtrate evaporated, and the residue partitioned between 2N NaOH and EtOAc. The organic phase was washed with saturated NaCl, dried (Na2SO4), and evaporated to yield 0.40 g of crude 2-(2-aminoethyl compound as a yellow oil. This oil was immediately dissolved in 60 mL of PhCH3, 50 mg of p-TSA was added, and the resulting mixture refluxed for 24hr with a Dean-Stark water separator. The reaction mixture was cooled to 25° , the volatiles were removed in vacuo, and the residue partitioned between saturated NaHCO3 and EtOAc. The EtOAc layer was washed with saturated NaCl, dried (Na2SO4), and evaporated to yield 383 mg of 10-phenyl-1,2,4,5-tetrahydro-10H-imidazo[1,2-b]benzazepine free base (19%) as a viscous yellow oil. Conversion to the hydrochloride salt (EtOH/ethanolic HCl) produced as white amorphous solid, mp ~150° (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)[CH:17]=[CH:16]2
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-n2ccc3cc(Br)ccc32)cn1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
5-Bromo-2-(trifluoromethyl)pyridine (2.075 g, 9.18 mmol) was added to a solution of 5-bromo-1H-indole (1.5 g, 7.65 mmol) and in DMF (20 mL) followed by cesium carbonate (7.48 g, 22.95 mmol), and the mixture was stirred at 90° C. for 15 min. Insoluble solids were filtered, filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 5% ethyl acetate in pet ether to afford title compound (1.1 g, 42.1%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.09 (d, J=2.4 Hz, 1H), 8.37 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.91 (m, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.37 (dd, J=1.8 Hz, J2=8.4 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[OH-].[Na+].[O:27]1CCOCC1.Cl>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[CH:9][CH:10]=2)[C:5]([OH:27])=[N:4][N:3]=1
Reactant: FC(F)(F)c1cccc(CNc2ccc3c(Cl)nnc(Cl)c3c2)c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nnc(Cl)c2ccc(NCc3cccc(C(F)(F)F)c3)cc12
Temperature: 85 °C

Procedure:
A mixture of (1,4-Dichloro-phthalazin-6-yl)-(3-trifluoromethyl-benzyl)-amine (39 mg, 0.105 mmol), 2N NaOH (0.52 mL, 1.05 mmol) and dioxane (3 mL) was heated to 85° C. for 64 hours. The reaction was diluted with water, acidified with conc. HCl to ˜pH 4 and extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Chromatography (Hex/EtOAc) afforded 4-chloro-7-(3-trifluoromethyl-benzylamino)-phthalazin-1-ol (13 mg), 1H NMR (600 MHz, CDCl3) δ: 4.36 (d, 2H), 6.25 (t, 1H), 7.00 (dd, 1H), 7.22 (d, 1H), 7.28-7.42 (m, 3H), 7.46 (s, 1H), 7.57 (d, 1H), 11.49 (s, 1H) ppm. m/z 354.08; and 4-chloro-6-(3-trifluoromethyl-benzylamino)-phthalazin-1-ol (8 mg), 1H NMR (500 MHz, CDCl3) δ: 4.36 (d, 2H), 6.28 (t, 1H), 6.74 (d, 1H), 6.92 (dd, 1H), 7.32-7.46 (m, 3H), 7.51 (s, 1H), 7.95 (d, 1H), 11.60 (s, 1H) ppm. m/z 354.08.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12]C)=[O:11])=O.O.[NH2:19]N>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10]([OH:12])=[O:11])=[N:19]1
Reactant: NN
Reactant: COC(=O)c1ccnc(C(=O)/C=C\N(C)C)c1
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccnc(-c2cc[nH]n2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a 2 L three-necked flask was added (Z)-methyl 2-(3-(dimethylamino)acryloyl)isonicotinate (0.894 mol), hydrazine hydrate (48.8 g), anhydrous ethanol (1 L). The suspension was stirred at 20° C. overnight. The solvent was removed in vacuo. The residue was taken up in concentrated hydrochloric acid (600 mL) and heated to reflux for 2 hours. The mixture was cooled to ambient temperature. The resultant precipitate was filtered, washed with water, ethanol and acetone and dried to give 78.6 g of the title compound as a brown solid. 1HNMR (DMSO-d6/D2O) δ ppm 8.80 (d, 1H), 8.50 (s, 1H), 7.91 (d, 1H), 7.87 (dd, 1H), 7.15 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[Cl:18])=[C:8]([Cl:19])[C:7]([NH2:20])=[N:6][CH:5]=1.Cl[CH:23]([CH:26]=O)[CH:24]=[O:25]>>[CH3:1][O:2][C:3]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[Cl:18])=[C:8]([Cl:19])[C:7]2[N:6]([C:23]([CH:24]=[O:25])=[CH:26][N:20]=2)[CH:5]=1)=[O:21]
Reactant: O=CC(Cl)C=O
Reactant: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(Br)cc1Cl
Product: COC(=O)c1cn2c(C=O)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 80 °C

Procedure:
A suspension of 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloro-nicotinic acid methyl ester (28) (1.06 g, 2.72 mmol) and 2-chloro-malonaldehyde (587 mg, 5.43 mmol) was heated to 80° C. for 45 minutes. The solution was allowed to cool to room temperature, and then washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over NaSO4, filtered, concentrated in vacuo, and purified by column chromatography (20:1 methylene chloride/methanol) to give the desired product as a dark yellow solid. The solid was triturated with ethyl acetate and isolated by filtration to provide the desired product as a yellow solid (0.436 g, 36%). MS (APCI+) m/z 442, 444, 446 (M+; Cl, Br pattern) detected.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)OC(C)(C)O2
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2ccc(C(=O)CBr)cc2O1
Reaction time: 15 h

Procedure:
Bromine (1.5 cc) is added in the course of 5 minutes at a temperature in the region of 20° C. to a stirred solution of 5-acetyl-2,2-dimethyl-1,3-benzodioxole (5.8 g) in carbon tetrachloride (100 cc), and the mixture is left with stirring for 15 hours at the same temperature. The reaction mixture is taken up with water (150 cc). The organic phase is separated off after settling has taken place, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). 5-(2-Bromoacetyl)-2,2-dimethyl-1,3-benzodioxole (7.1 g) is obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:32])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O>[CH:1]([C:4]1[N:5]=[C:6]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:32])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(N(C)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
The obtained N-[4-[3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]thiazol-5-yl]propionyl]phenyl]-N-methyl-2-nitrobenzenesulfonamide (230 mg, 0.372 mmol) was dissolved in anhydrous dimethylformamide (5 mL). Potassium carbonate (154 mg, 1.116 mmol) and thiophenol (46 μL, 0.446 mmol) were added to the solution. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (8:2, v/v) to give the desired compound (154 mg) as yellow crystalline product (yield 95%).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[N+]([NH:22][C:23](N)=[O:24])([O-])=O.O>C(O)C>[NH2:22][C:23]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1)=[O:24]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 65 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 100 ml of 95% ethanol was treated with 1.73 g of nitrourea and then stirred at 65° C. for five hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvents afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The resultant solid was recrystallized from hot isopropanol to yield 3.41 g (73.3%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 170°-172° C.
Reaction SMILES: N1CCC[C@H]1[C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=O.Cl.[OH-].[Na+]>C1COCC1>[N:6]1([CH2:3][C@H:5]2[CH2:9][CH2:8][CH2:7][NH:6]2)[CH2:7][CH2:8][CH2:9][CH2:5]1
Reactant: O=C([C@@H]1CCCN1)[C@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C1CN[C@@H](CN2CCCC2)C1
Temperature: 0 °C

Procedure:
2-(R)-Prolylpyrrolidine (1.2 g, 7.1 mmol) was dissolved in THF (10 ml). The reaction mixture was cooled to 0° C. and BH3, 1M in THF (10 ml, 10 mmol) was dropwise at 0 C. The reaction mixture was refluxed for 16 h, 3 M HCl (4.7 ml). 2 M NaOH solution was added until pH 10 was reached. The product was extracted with 5% MeOH in CH2Cl2 (three times). The organic layers were dried over Na2SO4 and the solvent was removed to provide the title compound as a slightly yellow liquid (73%), which was used without further purification for the next step.