Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]>CCOCC>[CH3:7][N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CN(C)CCCCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)CCCCCN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of lithium aluminum hydride (8 ml, 0.5M in ether) is added, slowly, a solution of 5-(dimethylamino)-pentanenitrile (126 mg, 1 mmol, reference example 94a) in ether (1 mL). On complete addition, the cold bath is removed and stirring continued for 2 h. The reaction mixture is then cooled to 0° C. and quenched by dropwise addition of water (160 mL), sodium hydroxide solution (160 mL, 5M), then a further portion of water (160 mL). The resulting mixture is filtered through celite and the filtrate concentrated under reduced pressure to give an oil which is used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][C:8]2[C:16]([F:17])=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:32]([O:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:12]([C:11]2[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=3)=[N:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=3)=[C:16]([F:17])[CH:15]=2)=[O:14])[CH2:45][CH2:46]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: N#Cc1ccc(Oc2nc(Oc3cccc(OC(F)(F)F)c3)c(C(=O)O)cc2F)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(F)c(Oc3ccc(C#N)cc3)nc2Oc2cccc(OC(F)(F)F)c2)CC1
Yield: 57.1 %

Procedure:
6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy)nicotinic acid (1.3 g, 2.99 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.684 g, 3.0 mmol) were coupled using the procedure of Example 5(c) to afford 1.1 g of the required product. 1HNMR (DMSO-d6): δ 1.2 (2H, m), 1.4 (9H, d), 1.5 (2H, m), 1.6 (2H, m), 2.2 (1H, m), 2.35 (1H, m), 3.0 (3H, m), 3.7 (1H, m), 4.45 (1H, m), 6.78 (1H, m), 7.18 (1H, m), 7.26 (2H, m), 7.32 (1H, s), 7.46 (1H, m), 7.76 (1H, m), 7.86 (1H, s), 8.1 (1H, m).
Reaction SMILES: C([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.C(Cl)(=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:6]([NH:8][CH:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:5])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)OC(C)(C)C)CC2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as Example 16, Step A and B, 1-(RS)-((t-butoxycarbonyl)amino)-3-(SR)-((4-(N-(4-nitrobenzylaminocarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane from Example 22 (derived from the lower isomer from Example 20, Step E) was deblocked and acylated with benzoyl chloride to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][CH2:4][C:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[CH:6][O:7]C.O1CCCC1.Cl.[OH-].[Na+]>C(OCC)C>[F:26][C:2]([F:1])([F:25])[CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH:6]=[O:7]
Reactant: COC=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 91.7 %

Procedure:
A solution of 5-(4,4,4-trifluoro-1-methoxymethylene-butyl)-2-(4-trifluoromethyl-phenyl)-pyridine (4.1 g, 10.9 mmol) and tetrahydrofuran (50 mL) is treated with concentrated hydrochloric acid (5 mL) and heated to reflux under nitrogen. The reaction is monitored by HPLC and allowed to cool upon completion. The solution is neutralized with 20% NaOH solution and diluted with diethyl ether. The two phases are separated and the organic layer washed with brine and water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. Chromatography gives purified 5,5,5-trifluoro-2-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentanal (3.6 g, 10 mmol) 79% yield.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[N:13]=2)=[CH:10][N:11]=1)[CH2:5][OH:6].C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)(Cl)Cl>[Br:18][C:14]1[N:13]=[C:12]([C:9]2[S:8][C:7]([C@@H:4]3[CH2:5][O:6][C:27](=[O:29])[NH:3]3)=[N:11][CH:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](CO)c1ncc(-c2cccc(Br)n2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1N[C@H](c2ncc(-c3cccc(Br)n3)s2)CO1
Temperature: -78 °C
Reaction time: 2 h
Yield: 232.2 %

Procedure:
To a solution of (S)-2-amino-2-[5-(6-bromopyridin-2-yl)thiazol-2-yl]ethanol dihydrochloride (1.00 g, 2.68 mmol) obtained in Step 3, triethylamine (3.7 ml, 2.68 mmol) in chloroform (15 ml), a solution of triphosgene (278 mg, 0.94 mmol) in chloroform (5 ml) was added dropwise while cooled to −78° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was warmed to room temperature and water was added and it was extracted with ethyl acetate. After washed with a saturated brine, the organic layer was dried over magnesium sulfate. After concentrated, the residue was purified by flash chromatography on silica gel (chloroform:methanol:ethyl acetate=15:1:1) and the title compound (712 mg, 82%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([C:30]([N:32]1[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33]1)=[O:31])[C@H:9]([CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([N:27]=[CH:28][N:29]=3)[CH:26]=2)=[CH:17][CH2:16]1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([C:30]([N:32]1[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33]1)=[O:31])[C@H:9]([CH:15]1[CH2:16][CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([N:27]=[CH:28][N:29]=3)[CH:26]=2)[CH2:19][CH2:20]1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H](C1CC=C(c2ccc3ncnn3c2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)[C@@H](C1CCC(c2ccc3ncnn3c2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reaction time: 24 h

Procedure:
The material from Step C (0.79 g, 1.5 mmol) was placed under 1 atmosphere of hydrogen gas in the presence of 10% palladium on carbon (1.6 g) in methanol (40 mL). After 24 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a mixture of cis and trans diastereomers. These diastereomers were separated by chiral HPLC (Chiralcel OD column eluting with 20% isopropanol in heptane) to afford the title compounds as single isomers (Analytical retention times: Diastereomer A Tr=11.8 min, Diastereomer B Tr=13.9 min. LC/MS 549.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
Tetrakis(triphenylphosphine)palladium (577 mg; 0.5 mM) was added to 3,5-dibromopyridine (5.214 g; 22 mM) in 40 mL of toluene at R.T. under nitrogen. After 10 minutes stirring, 25 mL of 2M aqueous sodium carbonate solution, phenylboronic acid (2.44 g; 20 mM), and 10 mL of ethanol were added, and the mixture was heated 11 hours at 80° C. The reaction mixture was cooled, diluted with 75 mL of ethyl acetate and washed with 2×15 mL of saturated sodium carbonate solution, and then dried over anhydrous magnesium sulfate. Solvent removal gave crude product, which was chromatographed on silica gel using ethyl acetate:hexane (1:5) mixture to give a white solid boiling at 100°-101° C./~0.1 mm in 28% yield.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:6]=1[S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16].O1CCCC1.[OH-].[Li+]>CO.O>[CH3:14][O:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[C:6]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)(=[O:16])=[O:17])[CH:7]=1
Reactant: COC(=O)Cc1cc(OC)c(OC)cc1S(=O)(=O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)O)c(S(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
{4,5-Dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetic acid methyl ester (0.3 g) was taken up in methanol (10 ml), tetrahydrofuran (10 ml) and water (10 ml). Lithium hydroxide (125 mg) was added and the reaction stirred at RT for 16 hrs. The reaction was diluted with water (10 ml), its volume reduced to one third in vacuo, and the reaction extracted with diethyl ether (3×15 ml). The aqueous layer was acidified to pH 4 with 2M hydrochloric acid and extracted with ethyl acetate (4×25 ml). The combined ethyl acetate extracts were washed with water (25 ml) and brine (25 ml) and dried over sodium sulphate. The solvent was removed in vacuo to yield the title compound as a white solid (291 mg, 100%).
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2[C:4](=NCCC2)[CH2:3][CH2:2]1.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15]CC.CCCCCCCCCC>CCCCCC>[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:10][CH2:11][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCCCO
Solvent: CCCCCCCCCC
Solvent: CCCCCC
Product: CCCCCCCCCCO
Reaction time: 1 h

Procedure:
In an inert atmosphere, 26.8 mmol each of DBU (95 ppm H2O) and 1-hexanol (26 ppm H2O) were charged into a flame-dried flask. N-Decane (2 mL, undried) was added and was found to be miscible at room temperature; only one homogeneous liquid phase was observed. CO2 (H2O<5 ppm) was slowly bubbled through the decane/1-hexanol/DBU mixture at 1 bar overnight. The resultant mixture appeared split into two separate liquids. Argon was then bubbled through the two-phase liquid mixture for 1 h at 35° C. After 1 h, the two liquids had merged into one liquid. A schematic representation of this reversible reaction appears in FIG. 4. Similar experiments were performed with hexane in place of decane and with several alcohols (1-propanol, 1-butanol, 1-hexanol, 1-octanol, and 1-decanol) in place of 1-hexanol; similar results were obtained except that with 1-decanol, no phase split was observed even after the treatment with CO2. Miscibility data for alcohol/DBU systems is presented in Table 1.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])[C:9](=O)[O:10]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N(CCc1ccccc1Br)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2cccc(Br)c2CCN1Cc1ccccc1
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
0.5 g of methyl benzyl[2-(2-bromophenyl)ethyl]carbamate is dissolved under an inert atmosphere in 20 cm3 of dichloromethane at a temperature close to 20° C. 0.526 g of N,N-dimethylpyridin-4-amine is added, then the reaction mixture is cooled to a temperature close to 0° C. 1.2 cm3 of trifluoromethanesulfonic anhydride is introduced dropwise. The suspension obtained is stirred for 15 min at a temperature close to 0° C., then for 4 h 30 min while allowing it to gradually climb back up to a temperature close to 20° C. Dichloromethane is added to the reaction mixture and also a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate then concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained (1 g) is purified by flash chromatography over silica (column: 90 g; particle size: 15-40 μm; eluent: 100% dichloromethane to 95% dichloromethane/5% ethyl acetate gradient). After concentrating the fractions under reduced pressure, 0.22 g of 2-benzyl-5-bromo-3,4-dihydroisoquinolin-1(2 H)-one is obtained.
Reaction SMILES: B(O[O-])=[O:2].[Na+].[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:40])[N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][C:28](B5OC(C)(C)C(C)(C)O5)=[CH:27][N:26]=4)[CH:20]=3)[N:17]=2)[CH:9]=[N:8]1>C1COCC1.O>[OH:2][C:28]1[CH:27]=[N:26][C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[CH2:18][N:16]2[C:15](=[O:40])[CH:14]=[CH:13][C:12]([C:10]3[CH:9]=[N:8][N:7]([CH3:6])[CH:11]=3)=[N:17]2)=[N:30][CH:29]=1
Reactant: O=BO[O-]
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(B5OC(C)(C)C(C)(C)O5)cn4)c3)n2)cn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.50 g (85.1 mmol) of sodium perborate are added in portions with ice-cooling to a suspension of 13.4 g (28.4 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one in 55 ml of THF and 55 ml of water, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is filtered off through kieselguhr with suction. The filtrate is evaporated to about half of the original volume in vacuo and adjusted to a pH of 1 using 2 N hydrochloric acid. The precipitate formed is filtered off with suction, washed with water and dried in vacuo: 2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one as pale-beige crystals; m.p. 239° C.; ESI 361.
Reaction SMILES: Br[CH:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[OH:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:17]=[C:16]([CH2:36][OH:37])[N:15]=1>>[OH:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][CH:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:17]=[C:16]([CH2:36][OH:37])[N:15]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCOc1cc(CO)nc(CO)c1
Reactant: CC(Br)CC(=O)OC(C)(C)C
Product: CC(CC(=O)OC(C)(C)C)NCCOc1cc(CO)nc(CO)c1

Procedure:
Prepared as for Ex. 2, starting with tert-butyl 3-bromo-butyrate and N-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-2-nitro-benzenesulfonamide:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:36])[NH:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:20][C:19]=2[N+:37]([O-])=O)=[C:11]([Cl:40])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(OP(OCC)OCC)C>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:37][C:19]3[C:18]([CH:17]=2)=[CH:23][CH:22]=[C:21]([C:24](=[O:36])[NH:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=2)[CH:20]=3)=[C:11]([Cl:40])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(/C=C/c2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[N+](=O)[O-])c(Cl)c1
Agent: CCOP(OCC)OCC
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2cc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3,5-dichloro-4-{(E)-2-[2-nitro-4-(quinolin-2-ylcarbamoyl)-phenyl]-vinyl}-phenyl)-propionic acid tert-butyl ester (200 mg, 0.34 mmol) was added triethylphosphite (300 μL) and the mixture was stirred at 160° C. for 3 h. The solvent was removed under reduced pressure and the residue was taken up in toluene and concentrated twice. The crude material was purified by flash chromatography on silica gel, eluting with a gradient of 2-100% ethyl acetate/heptane to obtain 3-{3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-indol-2-yl]-phenyl}-propionic acid tert-butyl ester as a yellow solid. MS (m/z) 560.2 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.81 (d, J=1.52 Hz, 1H), 11.04 (s, 1H), 8.39 (s, 2H), 8.20 (s, 1H), 7.94 (d, J=1.14 Hz, 1H), 7.88 (d, J=8.08 Hz, 1H), 7.80 (dd, J=8.34, 1.52 Hz, 1H), 7.73 (ddd, J=8.37, 6.92, 1.39 Hz, 1H), 7.68 (d, J=8.46 Hz, 1H), 7.55 (s, 2H), 7.52 (t, J=6.95 Hz, 1H), 6.57 (d, J=1.39 Hz, 1H), 2.90 (t, J=7.33 Hz, 2H), 2.62 (t, J=7.45 Hz, 2H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][C:9]=1[F:11])[NH:6][CH2:5][CH2:4]2
Reactant: Fc1cc(F)c2c(c1)NCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Fc1cc2c(c(F)c1Br)CCN2
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4,6-difluoroindoline (4.6 g, 29.8 mmol) in acetonitrile (50 mL) was added a solution of N-bromosuccinimide (3.68 g, 20.6 mmol) acetonitrile (30 mL) at 0° C. dropwise. The reaction was stirred for 30 minutes and quenched with saturated aqueous sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated and the organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound (4.0 g, 58% yield) as colorless oil
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14]1([CH:20]2[CH2:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:23]2[C:22](=[O:27])[CH2:21][CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][C:24]2=[O:26])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC(c2ccccc2)CC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (4.4 g) in dry dichloromethane (5 ml) was added at 5°-10° C. to a stirred solution of 5-phenylcyclohexane-1,3-dione [3.7 g] and triethylamine (2.8 ml) in dry dichloromethane (50 ml), and the mixture was stirred at ambient temperature for 18 hours. Triethylamine (8.4 ml) and acetone cyanohydrin (0.4 ml) were added successively to the solution and the mixture was stirred at ambient temperature for 4 hours. The resulting solution was washed successively with 2N hydrochloric acid (25 ml) and water (3×25 ml), dried over sodium sulphate and evaporated under reduced pressure to give a brown solid which was recrystallised from acetonitrile to give 2-(4-chloro-2-nitrobenzoyl)-5-phenylcyclohexane-1,3-dione (4.2 g), mp 144°-145° C., as a light cream crystalline solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:15]([OH:17])=O)[CH3:2].Cl.[CH3:19][NH:20][O:21][CH3:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[N:5][C:4]=1[C:15](=[O:17])[N:20]([O:21][CH3:22])[CH3:19])[CH3:2]
Reactant: CCc1[nH]c(-c2ccc(F)cc2)nc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1[nH]c(-c2ccc(F)cc2)nc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A mixture of 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylic acid (600 mg), N,O-dimethylhydroxylamine hydrochloride (325 mg), 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride (540 mg), 1-hydroxybenzotriazole (381 mg) and triethylamine (0.54 ml) in N,N-dimethylformamide (9 ml) was stirred at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane:ethyl acetate=2:1) to obtain 5-ethyl-2-(4-fluorophenyl)-4-(N-methoxy-N-methylcarbamoyl)imidazole (656 mg) as colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 39.5 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (2.8 g, 8.0 mmols), ethyl 3-bromopropionate (2.1 ml, 16 mmols), potassium carbonate (1.1 g, 8.0 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 3-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminopropionate (1.42 g, 39.6%).