Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:25][C:26]([F:29])([F:28])[F:27]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCC(F)(F)F)c1
Temperature: 150 °C
Yield: 35.4 %

Procedure:
To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (2.5 g) in acetonitrile (0.5 mL) and DMF (10 mL) in a microwave tube was added potassium carbonate (2.93 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.79 g). The mixture was heated to 150° C. in a microwave oven for 30 minutes. The solvent was removed in vacuum, ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Recrystallization of the residue from ethanol gave 1.2 g of the title compound. The mother liquor was concentrated in vacuum and purified by aminophase-silica-gel chromatography followed by recrystallized from methanol and water to give further 0.64 g of the title compound.
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1.Cl>CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:19])[CH2:17][CH2:18][O:14][CH2:15]1
Reactant: O=C1CCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCOC1
Temperature: 0 °C
Yield: 44.1 %

Procedure:
Tetrahydrofuran (55 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (2.404 mL, 16.26 mmol) was then added and stirred under N2 and then cooled to 0° C. Dihydrofuran-3(2H)-one (1 g, 11.62 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.116 mL, 0.116 mmol) was added dropwise slowly via syringe and allowed to warm up to RT for 1 hr. The reaction was then cooled back down to 0° C. and added 30 mL of 1N HCl and stirred at RT for overnight. The reaction was then diluted with EtOAc and separated with water. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give the product 3-(trifluoromethyl)tetrahydrofuran-3-ol (800 mg, 44.1% yield) as an orange thin oil. 1H NMR (400 MHz, CHLOROFORM-d) d 4.05-3.92 (m, 3H), 3.80-3.75 (m, 1H), 2.31 (dt, J=13.3, 8.4 Hz, 1H), 2.08-2.03 (m, 1H).
Reaction SMILES: OC(CCCCCC)/C=C/[CH:5]1[CH:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][C:7](=[O:13])[CH:6]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C(O)=O.[C:30]([O:34][C:35](=[O:38])[CH2:36][CH3:37])(=O)[CH2:31][CH3:32].C([O:42][C:43](=[O:45])C)(=O)C>>[C:35]([O:34][CH:30]([CH2:10][CH2:9][CH2:5][CH2:6][CH2:7][CH3:8])[CH:31]=[CH:32][CH:5]1[CH:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][C:7](=[O:13])[CH:6]1[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:43]([OH:42])=[O:45])(=[O:38])[CH2:36][CH3:37]
Reactant: CCC(=O)OC(=O)CC
Reactant: CCCCCCC(O)/C=C/C1C(CCCCCCCC(=O)O)C(=O)CC1C(C)C
Reactant: CC(=O)OC(C)=O
Product: CCCCCCC(C=CC1C(C(C)C)CC(=O)C1C(CCCCCC)C(=O)O)OC(=O)CC

Procedure:
In the same manner but using the appropriate choice of compound of formula I (R1 =H) and lower alkanoic anhydride, then other compounds of formula I (R= lower alkanoyl and if R2 is CH2OR3 then R3 is lower alkanoyl) are prepared. For example the choice of trans-8-[2-(3-hydroxy-1-nonenyl)-3-isopropyl-5-oxocyclopentyl]octanoic acid (Example 144) and propionic anhydride instead of the compound of formula I and acetic anhydride noted in the procedure of this Example, give trans-8-[(2-(3-propionoxy-1-nonenyl)-3-isopropyl-5-oxocyclopentyl]octanoic acid. Similarly, ethyl trans-8-[2-3-hydroxy-1-heptenyl)-5-oxocyclopentyl]-6-octynoate (see Example 161) and butyric anhydride gives ethyl trans-8-[2-(3-butyryloxy-1-heptenyl)-5-oxocyclopentyl]-6-octynate.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N:21]1([CH:2]([CH3:4])[CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(C2=C(CC(C)N3CCCC3)C(=O)NCCC2)c1

Procedure:
The solution of 1.36 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 0.52 g of pyrrolidine and 0.1 g of p-toluenesulfonic acid hydrate in 10 ml of benzene is refluxed with water separation for 4 hours and evaporated. The residue is dissolved in 15 ml of ethanol and the solution hydrogenated over 0.1 g of platinum oxide at atmospheric pressure and room temperature. The mixture is filtered, the filtrate evaporated and the resulting oil dissolved in 2 N hydrochloric acid. The solution is washed with benzene, basified with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from petroleum ether and hexane, to yield the 3-(2-pyrrolidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 94° to 96°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH3:14])[C:3]=1[I:13]
Reactant: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(Cl)c1I
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (16 g, 47 mmol) and potassium carbonate (17 g, 120 mmol) in DMF (40 mL) was treated with methyl iodide (6.4 mL, 100 mmol) and stirred at 60° C. for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (twice). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated to give a crude solid. The crude material was purified by flash column chromatography using EtOAc in hexanes (5%-30%) to give the desired product (14 g, 84%) as an orange solid. LCMS for C9H8Cl2IO2 (M+H)+: m/z=344.9, 346.9. Found: 344.8, 346.9.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18](OC(=O)C)(=[O:20])C.C(OC=O)=O.CCOCC>O1CCCC1.C(Cl)(Cl)Cl>[CH:18]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:20]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: CC(=O)OC(C)=O
Agent: O=COC=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC=O)C2
Temperature: 70 °C
Yield: 37.9 %

Procedure:
To a suspension of (-)-aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (965 mg, 4.19 mmol) in a mixture of tetrahydrofuran (30 ml) and chloroform (30 ml), acetic anhydride--formic anhydride (1.83 g, 20.8 mmol) was added and refluxed with heat in a bath of 70° C. for 3 hours. The temperature of the reaction mixture was returned to room temperature. Ether was added to the mixture and insoluble matter was collected by filtration. Recrystallization from chloroform--methanol--ether yielded 410 mg of the title compound as colorless powder (37.9%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[N:14][OH:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(C=NO)cc1
Yield: 98.3 %

Procedure:
A suspension of methyl 4-formylbenzoate (4.92 g), hydroxylamine hydrochloride (5.21 g) and sodium acetate (6.15 g) in ethanol (50 ml) was refluxed for 2 hours. The mixture was poured into water and extracted with ethyl acetate and the separated organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure to give 4-methoxycarbonyl-benzaldehyde oxime (5.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:10][CH3:11])[CH:3]=1.F[C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:18]2[CH:19]=[N:20][CH:21]=[CH:13][C:14]=2[C:15]([OH:17])=[O:16])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: COc1cc(Cl)ccc1CN
Product: COc1cc(Cl)ccc1CNc1cnccc1C(=O)O
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 4-chloro-2-methoxy-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 8.10 (s, 1H), 8.00 (br s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.24 (d, 1H, J=8.1 Hz), 7.11 (d, 1H, J=1.9 Hz), 6.96 (dd, 1H, J=8.0, 1.9 Hz), 4.47 (s, 2H), 3.87 (s, 3H). [M+H] calc'd for C14H13ClN2O3, 293, 295. found 293, 295.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([C:23](O)=[O:24])[CH2:18]2)[CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:3]4[N:2]([CH3:1])[C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=4)[CH:12]=3)[CH2:18]2)=[O:24])[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: Cn1c(-c2cccc(N3CCC[C@H](C(=O)O)C3)c2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1c(-c2cccc(N3CCC[C@H](C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)C3)c2)nc2ccccc21
Temperature: 35 °C
Yield: 26.5 %

Procedure:
Method A—Step a To a vial with (S)-1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid (0.10 g, 0.30 mmol) (obtained as described in general method 1, step d), HATU (0.12 g, 0.31 mmol), TEA (0.09 mL, 0.66 mmol) and tert-Butyl-1-piperazinecarboxylate (0.07 g, 0.37 mmol) dichloromethane (2 mL) was added and the reaction mixture was heated at 35° C. overnight. Reaction was cooled to room temperature, solvent removed and the crude purified by preparative HPLC and NH2 column filtration, to obtain 0.04 g of the title compound (27%).
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[CH:12]([CH3:14])[CH3:13].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:17][O:18][CH3:19])[C:4](=[O:11])[C:3]=1[CH:12]([CH3:13])[CH3:14]
Reactant: COCCl
Reactant: CCn1c(Cl)c(C(C)C)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(Cl)c(C(C)C)c(=O)n(COC)c1=O
Reaction time: 0.67 h
Yield: 91.2 %

Procedure:
To a stirred solution of 6-chloro-1-ethyl-5-isopropyl-1H-pyrimidine-2,4-dione (11.5 g, 53 mmol) in DMF (100 mL) in a water bath, was added 60% NaH (3.18 g, 79.6 mmol). After stirring for 40 min., technical grade chloromethyl methyl ether (7.6 mL, 80 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:5)) to give 12.6 g (91%) of 6-chloro-1-ethyl-5-isopropyl-3-methoxymethyl-1H-pyrimidine-2,4-dione as a colorless oil. H-NMR (200 MHz, CDCl3) δ 1.26-1.34 (9H, m), 3.24 (1H, m), 3.44 (3H, s), 4.16 (2H, q, J=7.0 Hz), 5.35 (2H, s); m/z (EI) 260 (M+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C=O)C>[C:21]12([CH2:20][CH2:19][NH:4][C:3]3[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=3[F:1])[CH2:22][CH:23]3[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]3)[CH2:30]1)[CH2:28]2
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: BrCCC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
To a solution of 2-fluoro-4-nitroaniline (2.34 g, 15.0 mmol) in DMF (30 mL) were added K2CO3 (4.2 g, 30.4 mmol), KI (0.5 g, 3.01 mmol) and 1-(2-bromoethyl)adamantane (3.65 g, 15.0 mmol) and the mixture was stirred at 140° C. for 12 h. The mixture was then cooled to rt and filtered. The filtrate was diluted with 150 mL of DCM and washed with water (50 mL×3), brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a yellow solid (477 mg, 10%).
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH:3]=[CH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([NH:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[O:16])=[CH:10][N:9]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([N:5]([C:12]1[C:11]([C:15]([NH:17][C:18]2[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])=[O:16])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCNN
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A solution of 230 mg (2.7 mmol) of 3-butenylhydrazine in 10.5 mL of THF was cooled to 0° C. and treated sequentially with 800 mg (2.4 mmol) of 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 370 μl (2.6 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 25 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 99.5:0.5) to give the title compound 85. 1H-NMR (DMSO-d6) δ 3.17 (d, J=5.2 Hz, 2H), 3.31 (s, 2H), 3.80 (t, J=7.3 Hz, 2H), 5.04 (d, J=10.3 Hz, 1H), 5.13 (d, J=17.1 Hz, 1H), 5.77-5.88 (m, 1H), 7.35 (t, J=8.3 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 8.15 (s, 1H), 10.19 (s, 1H). Mass Spectrum (ESI) m/e=385.9 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:5]([O:18][CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].CS([C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[N:31]=1)(=O)=O.O>CN(C=O)C>[CH3:39][O:38][C:32]1[CH:33]=[C:34]([O:36][CH3:37])[N:35]=[C:30]([O:1][CH:2]([C:5]([O:18][CH3:19])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]#[N:4])[N:31]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(c1ccccc1)(c1ccccc1)C(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(OC(C#N)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile were dissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K2CO3 and 6.3 g (28 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for about 12 h, then poured into water and extracted with ethyl acetate. The combined organic phases were washed again with H2O, dried and concentrated. The residue obtained in this way was then purified by chromatography on silica gel (n-hepane/ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[NH2:44][C:45]1[S:46][C:47]([S:50][CH2:51][CH3:52])=[N:48][N:49]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:44][C:45]2[S:46][C:47]([S:50][CH2:51][CH3:52])=[N:48][N:49]=2)=[O:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCSc1nnc(N)s1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCSc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethylthio-1,3,4-thiadiazole (60 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 53 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][CH2:28][O:29]C5CCCCO5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:36])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:36])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: OCCn1cc(-c2ccc3ncc(Cc4c(F)cc5ncccc5c4F)n3n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,7-Difluoro-6-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Stage 170.1, 82.2 mg, 0.168 mmol) was dissolved in DCM (2 mL) and a solution of 4 N HCl in dioxane (0.126 mL) was added. The RM was stirred at rt for 1 h and the solvent was removed. It was then taken up with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The solvent was removed and the residue was diluted in MeOH. The solution was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound (tR 0.8 min (conditions 2), MH+=407, 1H-NMR in DMSO-d6: 8.92 (dd, 1H); 8.51 (d, 1H); 8.38 (s, 1H); 8.06 (t, 2H); 7.72 (d, 1H); 7.59 (dd, 1H); 7.57 (s, 1H); 7.51 (d, 1H); 4.55 (s, 2H); 4.20 (t, 2H); 3.78-3.73 (m, 2H), 3.13 (s, 1H)).
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)=[O:19])[CH:11]=3)[O:6]2)[CH2:5]1
Reactant: CN1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 70.8 %

Procedure:
A suspension of (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (400 mg, 1.29 mmol) in DCM (16 ml) was treated with TEA (0.30 ml, 2.2 mmol) and then with EDC (420 mg, 2.20 mmol), HOBt (297 mg, 2.20 mmol) and NH2OTHP (204 mg, 1.75 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (340 mg) as a light yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[N+:18]([C:21]1[N:25]=[CH:24][NH:23][N:22]=1)([O-:20])=[O:19]>CN(C=O)C.O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([N:23]2[CH:24]=[N:25][C:21]([N+:18]([O-:20])=[O:19])=[N:22]2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(C=O)ccc1-n1cnc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.9 %

Procedure:
To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reaction mixture was stirred at ambient temperature for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]−); IR (thin film) 2238, 1705, 1551, 1314 cm−1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([N:18]2[CH2:17][CH2:16][O:15][CH2:20][CH2:19]2)=[N:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(N2CCOCC2)nc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(N2CCOCC2)nc1
Yield: 56.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.042 g, 0.178 mmol), 6-morpholinonicotinoyl chloride (0.045 g; 0.178 mmol), and triethylamine (0.062 mL; 0.446 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) furnished 0.039 g (57%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide as a solid.