Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:9][C:10](=[O:31])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:30])[C@H:17]([CH3:29])[NH:18][C:19]([O:21]CC2C=CC=CC=2)=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](OC(=O)CC)(=O)[CH2:33]C>Br.C(O)(=O)C.C(Cl)(Cl)Cl.CCOCC>[CH:1]1([NH:9][C:10](=[O:31])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:30])[C@H:17]([CH3:29])[NH:18][C:19](=[O:21])[CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCCC1
Reactant: CCC(=O)OC(=O)CC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
2 g (0.0047 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclooctylamide were dissolved in 10 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 100 ml of anhydrous ether were added and an oil precipitated out of the solution. The ether layer was decanted off and the oil washed with 100 ml of anhydrous ether. The ether layer was again decanted off and the oil dissolved in 30 ml of dry pyridine. 1.2 g (0.0094 mol) of propionic anhydride were added and the solution was stirred at room temperature for 2 hours. The pyridine was removed by evaporation, 50 ml of toluene were added to the residue and the mixture was again evaporated in order to azeotropically remove any residual pyridine. The solid obtained was taken up in 100 ml of chloroform, the solution was washed with sodium chloride solution and dried over magnesium sulphate. The solution was then evaporated to yield an oil. This oil was dissolved in the minimum volume of ether and petroleum ether was added, whereby a white solid crystallised out of the solution. There was obtained 0.900 g (56.3%) of N-propionyl-L-alanyl-L-proline cyclooctylamide of melting point 142°-143° C.; [α]D20 =-120.3° (c=0.82% in methanol).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[N:14](C(OC(C)(C)C)=O)[C:13](=[O:22])[C@H:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1)(C(C)(C)C)(C)C>C(#N)C.O>[OH:8][CH2:9][C@H:10]1[NH:14][C:13](=[O:22])[C@H:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H](Cc2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CC#N
Solvent: O
Product: O=C1N[C@H](CO)C[C@H]1Cc1ccccc1

Procedure:
To 130 mg (0.34 mmol) of 5(S)-((t-butyldimethylsilyloxy)methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone in 5 ml of acetonitrile was added 0.1 ml of a solution of 48% HF in water. After 3 hr at room temperature the reaction was concentrated to dryness and diluted with 30 ml of an aqueous 10% NaHCO3 solution. This was extracted with EtOAc (2×30 ml), dried filtered and concentrated to afford the crude product.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@H:13]2[C@H:4]1[C:5](=[O:16])[O:6][C:7]1[C:8]([F:15])=[CH:9][CH:10]=[C:11]([F:14])[C:12]=12.[OH-:17].[Na+]>O>[F:15][C:8]1[C:7]2[O:17][CH2:2][C@H:3]3[C@@H:4]([C:5]([OH:16])=[O:6])[C@H:13]3[C:12]=2[C:11]([F:14])=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: O=C1Oc2c(F)ccc(F)c2[C@@H]2[C@H](CBr)[C@H]12
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
(1S,1aR,7bS)-1-(bromomethyl)-4,7-difluoro-1a,7b-dihydrocyclopropa[c]chromen-2(1H)-one (360 mg, 1.2 mmol) was mixed with the solution of NaOH (0.1 g, 2.5 mmol) in 5 ml of water and heated at stirring for 1 h at 90° C. After completion the reaction mixture was cooled down and extracted into diethyl ether (2×20 ml). Water phase was acidified with conc. HCl. The precipitate formed was collected by filtration to give 180 mg of pure product. Mother liquor was extracted into ether and washed with brine, dried over magnesium sulfate. Concentration gave additional 70 mg of product (containing up to 15% of impurities). Overall yield about 92%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1F
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) is added to a solution of 2-fluoro-4-chlorophenylboronic acid (1.25 g, 7.17 mmol) and 4-bromo-1-ethyl-2-nitrobenzene (1.50 g, 6.52 mmol) in 1,2-dimethoxyethane (12 ml) and the mixture is stirred at room temperature for 15 minutes. A solution of sodium carbonate (5.52 g, 52 mmol) in water (26 ml) is added and the mixture is heated to reflux for 17 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and the two phases separated. The organic phase is collected, the aqueous phase is extracted with ethyl acetate and the organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 4′-chloro-4-ethyl-2′-fluoro-3-nitrobiphenyl (1.795 g), used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[C:9](\[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[CH:34]([NH2:37])([CH3:36])[CH3:35].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH:34]([NH:37][C:10](=[O:12])/[C:9](/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1ccc(/C(=C\c2cccc(Br)c2)C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)/C(=C/c1cccc(Br)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid from Step 1 (24.9 g, 65 mmol) in toluene (250 mL) was added thionyl chloride (14.3 mL, 196 mmol) and triethylamine (34 mL, 245 mmol). After stirring at 21° C. for 0.5 h., isopropyl amine (28 mL, 327 mmol) was added. After a further 2 h at r.t., the mixture was cooled to 0° C. and was neutralised with saturated NH4Cl solution, then extracted with EtOAc. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 1:1 to pure EtOAc) yielded the (E)-N-isopropyl-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide compound.
Reaction SMILES: Br[C:2]([C:5](=[O:7])[CH3:6])=[CH:3]O.[NH2:8][C:9]([NH2:11])=[O:10]>CC(C)=O>[C:5]([C:2]1[O:10][C:9]([NH2:11])=[N:8][CH:3]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)C(Br)=CO
Reactant: NC(N)=O
Solvent: CC(C)=O
Product: CC(=O)c1cnc(N)o1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A mixture of 132.3 g (0.80 m) of 2-bromo-1-hydroxy-3-oxo-1-butene, 120.1 g (2.0 m) of urea, and 1.85 l of acetone was heated at reflux with overhead stirring for one hour. The mixture was concentrated and the oil residue was taken up into 600 ml of water, then made basic with concentrated ammonium hydroxide. After sitting at room temperature for 0.5 hour, a precipitate formed. This was collected, and dried in vacuo to give 61.1 g of crude product. The filtrate was again concentrated and the oil residue taken up in 50 ml of water and again made basic with concentrated ammonium hydroxide. After sitting overnight a second crop of crude product, amounting to 17.6 g was isolated. Both crops were combined and recrystallized from methanol to give 50.3 g (50%) of 5-acetyl-2-aminooxazole, m.p. 214°-215°.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:26]4[CH2:27][CH2:28][O:29][CH2:30][CH:31]=4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1.CN(C=O)C.[C:49](=O)([O-:51])[O-:50].[Na+].[Na+]>O.CCOC(C)=O.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>[F:33][C:2]([F:1])([F:32])[C:49]([OH:51])=[O:50].[O:29]1[CH2:30][CH:31]=[C:26]([C:15]2[CH:14]=[CH:13][C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:40]5[C:35]([F:34])=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:8][CH:9]=4)[C@@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:27][CH2:28]1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1ccc(C3=CCOCC3)cc12
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1ccc(-c3cccnc3F)cc12
Product: O=C(O)C(F)(F)F
Temperature: 85 °C

Procedure:
A resealable vial was charged with (R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (100 mg, 0.207 mmol; prepared by method AA1 as described in Example 2), tetrakis(triphenylphosphine)palladium (23.95 mg, 0.021 mmol) and 2-fluoropyridin-3-ylboronic acid (0.332 mmol). DMF (1036 μL) was added followed by 2 M aqueous sodium carbonate (311 μL, 0.622 mmol) and the vial was sealed and heated at 85° C. for 1 hr. The mixture was cooled to the RT, diluted with water (2 ml) and EtOAc (5 ml). The organic layer was loaded onto 2 g SCX-2 column and washed with ethyl acetate and MeOH. The material was released from the column using 2M ammonia in MeOH solution, concentrated and purified by reverse phase HPLC (Gilson, 15-90% MeCN in 0.1% aq. TFA) to afford (R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine 2,2,2-trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]([F:9])[CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN(C)c1cc(C)ncn1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)c1cc(C)ncn1
Yield: 56 %

Procedure:
4-Chloro-2-fluoroaniline (77 mg, 0.53 mmol) was added to a solution of 4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (140 mg, 0.35 mmol) in isopropanol (5 ml) and the mixture heated at reflux for 1 hour. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (95/5). The purified solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (75 mg, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.S(Cl)([Cl:14])(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[Cl:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cccc(OC)c1
Product: COc1ccc(Cl)c(OC)c1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Into a triple-necked flask of 500 cm3, provided with a magnetic stirring system, with a thermometer, with a calcium chloride trap and a dropping funnel, and cooled to 10° C., were introduced successively 97.5 (0.70 mole) of 1,3-dimethoxy benzene and then drop by drop 96.5 g (0.70 mole) of sulfuryl chloride. Once the addition was ended, the solution was brought back to ambient temperature and allowed to stand 2 h and then distilled.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][OH:13])[CH2:10]O.CC(O)C[CH2:18][CH:19]([OH:21])C.C(OC(=O)C)(=[O:25])C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH3:10])[C@H:12]([O:13][C:19](=[O:21])[CH3:18])[OH:25]
Reactant: OCC(O)(CO)c1ccc(F)cc1F
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)CCC(C)O
Solvent: O
Product: CC(=O)O[C@H](O)C(C)(O)c1ccc(F)cc1F
Temperature: 30 °C
Reaction time: 15 h

Procedure:
A 300 ml reaction vessel was charged with 5 g of 2-(2,4-difluorophenyl)-1,2,3-propanetriol, 100 ml of diisopropanol, 2.45 ml of acetic anhydride and 5 g of Novozym 435 made by NOVO NORDISK, Ltd. (derived from Candida antarctica, Enzyme No. 24). The resulting mixture was stirred at 30° C. for 15 hours. After 10 ml of water was added thereto, the reaction liquid was filtered to remove the enzyme. An organic layer of the filtrate was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give 1 g of (S)-2-(2,4-difluorophenyl)-1-acetoxy-1,2-propanediol. The optical purity thereof was 8% ee.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[F:9][CH:10]([F:21])[O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[F:9][CH:10]([F:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(OC(F)F)cc1
Reactant: NC1CCC(O)CC1
Product: O=C(NC1CCC(O)CC1)c1ccc(OC(F)F)cc1

Procedure:
4-(4-DIFLUOROMETHOXYBENZAMIDO)CYCLOHEXANOL is prepared following the procedure described in Example A-1 using corresponding molar equivalent quantities of 4-aminocyclohexanol and 4-difluoromethoxybenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([Cu])#[N:10]>CN(C=O)C>[OH:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=1)[C:9]#[N:10]
Reactant: N#C[Cu]
Reactant: Oc1cncc(Br)c1
Solvent: CN(C)C=O
Product: N#Cc1cncc(O)c1
Temperature: 135 °C
Yield: 38.5 %

Procedure:
A mixture of 5-bromo-pyridin-3-ol (9.94 mL, 54.0 mmol) and CuCN (7.4 g, 82.62 mmol) in DMF (20 mL) was heated at 135° C. for 5 hour. DMF was removed under reduced pressure, the residue was diluted with NH4OH (10 mL) at 0° C. The mixture was bubbled with ammonia gas for 1 hour, cooled to 0° C. and acidified with conc. HCl (35 mL) until pH reached to ˜4. The resulting mixture was extracted with EtOAc (5×100 mL). The organic layer was washed with water (2×100 mL) and brine (2×100 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow solid. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (2.5 g, 39%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.7 Hz, 1H), 7.61-7.57 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15].[OH-].[NH4+]>CCO>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:19][CH2:18][CH2:17][N:16]([CH2:20][CH3:21])[CH2:14][CH3:15])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 40 °C

Procedure:
Chloro-2,4-dinitrobenzene 1 (1.00 g, 4.937 mmol) was dissolved in anhydrous EtOH (20 mL) in a small argon purged flask and warmed in an oil bath to 40° C. Addition of N,N-diethylethylenediamine 2a (0.63 g, 5.430 mmol) occurred dropwise. The reaction was stirred at reflux for 24 hours then cooled to room temperature. The mixture was basified by the addition of aqueous 1M ammonium hydroxide solution to adjust pH to 10-11. The solid that precipitated was collected on a sintered glass funnel and briefly dried. Recrystallization of the crude solid from EtOH yielded a yellow powder 3a N′-(2,4-Dinitro-phenyl)-N,N-diethyl-ethane-1,2-diamine. Yield: 0.94 grams (67.4%). 1H NMR (DMSO) δ: 0.99 (t, 6H, J=7.1), 2.56 (m, 4H), 2.70 (t, 2H, J=6.1), 3.49 (q, 2H, J=5.5), 7.19 (d, 1H, J=9.7), 8.28 (dd, 1H, J=9.5, 2.6), 8.67 (d, 1H), 9.05 (br s, 1H); MS (APCI): 283 (MH+, 100%)
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=1[CH3:25])[CH:12]=2)[C:3]([O:5]C)=O.[NH2:32][C:33]([NH2:35])=[S:34].C([O-])(=O)C.[Na+]>C(O)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([CH2:7][CH:2]3[S:34][C:33](=[NH:32])[NH:35][C:3]3=[O:5])[CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: NC(N)=S
Reactant: COC(=O)C(Br)Cc1cnc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3SC(=N)NC3=O)cnc2c1

Procedure:
In ethanol (10 mL) was dissolved the crude residue (300 mg) of methyl 2-bromo-3-[7-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-quinolyl]propionate. The solution was heated under reflux for 5 hours after addition of thiourea (47 mg, 0.62 mmol.) and sodium acetate (51 mg, 0.62 mmol.).
Reaction SMILES: C(O)(C)(C)C.[CH3:6][O:7][CH2:8][CH:9]([NH2:12])[CH2:10][CH3:11].Cl[C:14]1[C:15]([N+:25]([O-:27])=[O:26])=[C:16]([CH3:24])[C:17]([CH3:23])=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>C(Cl)(Cl)Cl>[CH3:6][O:7][CH2:8][CH:9]([NH:12][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[C:16]([CH3:24])[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:10][CH3:11]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CCC(N)COC
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CCC(COC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
(-)-2-Amino-1-butanol [100 grams, prepared according to D. Pitre and E. B. Grabitz, Chimia 23, 399 (1969)] was added in a dropwise manner to a stirred solution of tert-butanol (800 ml.) containing potassium tert-butoxide (126 grams). After warming this mixture to 70° C. to 80° C. for 2 hours, methyl iodide (175 grams) was added slowly at temperatures below 50° C. The suspension which formed was then stirred with refluxing overnight. After removal of the solid phase by filtration, the filtrate was fractionally distilled to give (-)-1-(methoxymethyl)propylamine contaminated with traces of tert-butanol, boiling point 125° C. to 147° C./760 mm. This amine was then allowed to react with 4-chloro-3,5-dinitro-o-xylene, as described earlier, to give the desired product as a bright yellow solid with melting point 42.5° C. to 44° C., [α]D25° = -137.6° (c 2.504, chloroform).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[C:15]1[C:16]2[N:17]([CH:22]=[CH:23][N:24]=2)[N:18]=[C:19]([Cl:21])[CH:20]=1.O>CN(C=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([NH:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=2)[C:16]2[N:17]([CH:22]=[CH:23][N:24]=2)[N:18]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of 6-(trifluoromethyl)pyridin-2-amine (0.668 g, 4.12 mmol) in DMF (5 mL) was added NaH (0.10 g, 4.18 mmol) and stirred for 0.5 h. To the mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.38 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h then 100 mL of water was added and the precipitate collected by filtration and washed with water to give 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.513 g, 99%) as a light brown solid. LC-MS: [M+H]+, 314.1, tR=1.738 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18]
Reactant: O=C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 6 h
Yield: 53.4 %

Procedure:
3,4-Difluoro-1-nitrobenzene (0.50 mL, 4.52 mmol) was dissolved in 8 mL NMP. To it was added morpholin-3-one (0.91 g, 9.04 mmol) and cesium carbonate (2.95 g, 9.04 mmol). The mixture was stirred at 120° C. for 6 h. It was cooled to RT, diluted with 200 mL EtOAc, washed with brine three times, dried, concentrated in vacuo and subjected to silica flash column (0-30% EtOAc in DCM) to isolate 4-(2-fluoro-4-nitrophenyl)morpholin-3-one (580 mg, 53%). It was dissolved in 200 mL EtOAc and 100 mL MeOH. To it was added 500 mg 10% Pd/C. The mixture was stirred under a hydrogen balloon for overnight. The mixture was filtered through celite, and the solid cake was thoroughly washed with MeOH. The filtrate was concentrated in vacuo to afford 4-(4-amino-2-fluorophenyl)morpholin-3-one in quantitative yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of the product of Example 353E (16.1 mg, 0.036 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and ethanesulfonyl chloride was added (0.0036 mL, 0.038 mmol). The mixture was warmed to 23° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile in 0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (7.7 mg, 40%). The sodium salt of the title compound was prepared by adding 1 N sodium hydroxide (0.029 mL, 0.0029 mmol) to a solution of the title compound (7.7 mg, 0.014 mmol) in water (0.4 mL) and stirring for thirty minutes. The reaction mixture was concentrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (bs, 2 H) 0.46 (d, 2 H) 0.99 (m, 1 H) 1.19 (t, 3 H) 3.01 (q, 2 H) 4.23 (s, 2 H) 5.85 (t, J=6.62 Hz, 1 H) 6.79 (s, 1 H) 6.93 (t, J=7.54 Hz, 1 H) 7.35 (t, J=6.99 Hz, 2 H) 7.59 (d, J=8.09 Hz, 1 H) 7.95 (d, J=6.62 Hz, 1 H).