Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14]#N)=[N:10]2)=[C:5]2[NH:16][CH:17]=[CH:18][C:4]=12.[C:19]([O-])([O-])=[O:20].[K+].[K+].Cl.C[OH:27]>O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14]([O:20][CH3:19])=[O:27])=[N:10]2)=[C:5]2[NH:16][CH:17]=[CH:18][C:4]=12
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(-n2cnc(C#N)n2)c2[nH]ccc12
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1ncn(-c2ncc(OC)c3cc[nH]c23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
1-(4-Methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazole-3-carbonitrile (1 g, 4.16 mmol) and K2CO3 (0.863 g, 6.24 mmol) were combined in MeOH (20 mL) and water (20 mL). The mixture was stirred at room temperature overnight. The mixture was neutralized with 1N HCl to pH=3. The precipitate was collected by filtration to give methyl 1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazole-3-carboxylate (1.03 g, 3.77 mmol, 91% yield). LCMS: m/z 274.2 (M+H)+, 1.63 min (method 8). 1H NMR (500 MHz, MeOD) d ppm 9.22 (s, 1H) 7.47 (s, 1H) 7.39 (d, J=3.05 Hz, 1H) 6.62 (d, J=3.05 Hz, 1H) 4.03 (s, 3H) 4.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[C:4](=[O:9])[C:5]([Cl:8])=[CH:6][N:7]=1.[CH3:19][C@@:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:26][C@:20]1([CH3:19])[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[N:3]([CH2:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[C:4](=[O:9])[C:5]([Cl:8])=[CH:6][N:7]=2)[CH2:21]1
Reactant: C[C@@]1(N)CCCNC1
Reactant: N#Cc1ccccc1Cn1c(Cl)ncc(Cl)c1=O
Product: C[C@@]1(N)CCCN(c2ncc(Cl)c(=O)n2Cc2ccccc2C#N)C1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 2-(2,5-dichloro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile (Example 15B) and (R)-3-methyl-piperidin-3-ylamine according to the general procedure outlined for Example 1 and was isolated as the HCl salt. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (br s, 3H), 8.09 (s, 1H), 7.80 (d, 1H, J=7.6 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.22 (d, 1H, J=7.6 Hz), 5.39 (AB q, 2H, J=98.0, 14.8 Hz), 3.39-3.47 (m, 1H), 3.01-3.15 (m, 2H), 2.80-2.90 (m, 1H), 1.81-2.00 (m, 2H), 1.56-1.66 (m, 2H), 1.30 (m, 3H), MS (ES) [m+H] calc'd for C18H20N5OCl, 358, 360; found 358, 360.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:15]2[CH:20]=[C:19]([C:21]#[C:22][CH3:23])[C:18]([N:24]3C=NC=N3)=[N:17][C:16]2=[O:29])[CH2:6]1)(=O)C>O1CCOCC1.O>[C:21]([C:19]1[C:18]([NH2:24])=[N:17][C:16](=[O:29])[N:15]([CH:20]=1)[C@@H:7]1[O:8][C@H:9]([CH2:10][OH:11])[C@@H:5]([OH:4])[CH2:6]1)#[C:22][CH3:23]
Reactant: CC#Cc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](COC(C)=O)O2)c(=O)nc1-n1cncn1
Solvent: O
Solvent: C1COCCO1
Product: CC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1N
Reaction time: 16 h
Yield: 30 %

Procedure:
Crude product of stage b) (0.2 g, 0.5 mmol) was dissolved in 5 ml of Dioxan/880NH3 /H2O (3:2:1) and the mixture was left standing at room temperature for 16 hrs. It was then evaporated to dryness and the residue co-evaporated with ethanol. The resulting white solid was recrystallised from ethanol to give 0.04 g (30%) of pure product decomposing at 195°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:34])[C@H:30]([CH2:32][OH:33])[NH2:31])C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:26][O:28][C:29](=[O:34])[CH:30]([NH:31][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH2:32][OH:33]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.556 g (10 mmol) of L-serine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][S:15]SC.[OH-].[Na+]>CC(N(C)C)=O.[Cu]>[CH3:14][S:15][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CSSC
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CSc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A stirred mixture of 2-chloro-4-nitrobenzoic acid (24.2 g, 120 mmol), methyldisulfide (5.6 mL), copper powder (7.6 g) in 160 mL of DMA was heated to 135° C. during 1 hours, kept at that temperature for 90 minutes, and then heated at 165° C. for 2 hours. After the reaction was completed, the solvent was removed in vacuum to afford the crude compound, which was poured into 40% w/v aqueous sodium hydroxide solution. The mixture was filtered and the filtrate was washed with EtOAc and the aqueous layer was acidified with concentrated aqueous hydrochloric acid and filtered. The solid residue was washed with water and then dissolved in EtOAc, and the solution was dried over anhydrous Na2SO4 and evaporated to dryness under reduced pressure. The residue was crystallized from aqueous EtOH to give 2-(methylsulfanyl)-4-nitrobenzoic acid. 1H-NMR (400 MHz, MeOD) δ ppm 8.2˜8.33 (rn, 1H), 8.12˜8.17 (m, 1H), 7.95˜7.98 (m, 1H), 2.53 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#N.C(O)C.[OH-:22].[K+].Cl.[OH2:25]>C(Cl)Cl>[OH:1]/[N:2]=[C:3](\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:4]([OH:25])=[O:22]
Reactant: [OH-]
Reactant: O
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)/C(=N/O)c1ccccc1Oc1ccccc1
Yield: 60.9 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (0.71 g, 0,003 mole) were added ethanol (3 ml), potassium hydroxide (0.40 g, 0.0072 mole) and water (3 ml). After completion of the reaction, methylene chloride (10 ml) and 10% hydrochloric acid were added to the reaction mixture, and the crystals of α-hydroxyimino-2-phenoxyphenylacetic acid precipitated were filtered off to obtain colorless crystals (0.47 g, yield: 60.9 %).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[CH:9][C:10]([F:18])=[C:11]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:12]=1.[N+:19]([C:22]1[C:23]([CH:32]=[O:33])=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)([O-:21])=[O:20]>C1COCC1>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:11]1[CH:12]=[C:7]([CH:32]([C:23]2[C:22]([N+:19]([O-:21])=[O:20])=[C:31]3[C:26]([CH:27]=[CH:28][CH:29]=[N:30]3)=[CH:25][CH:24]=2)[OH:33])[CH:8]=[CH:9][C:10]=1[F:18]
Reactant: Fc1ccc(Br)cc1C1OCCO1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=[N+]([O-])c1c(C(O)c2ccc(F)c(C3OCCO3)c2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
Magnesium (983 mg, 40.5 mmol) was suspended in anhydrous THF (30 ml). 1,2-dibromoethane (0.17 ml, 2.02 mmol) was added and the solution was stirred at room temperature for 20 min. 2-(5-bromo-2-fluoro-phenyl)-[1,3]dioxolane 417 (3.2 g, 12.95 mmol) was added dropwise and the mixture was heated at 40° C. for 2 h. The mixture was allowed to cool to room temperature. The Grignard reagent (0.43M; 28.6 ml) was added to a suspension of 8-nitroquinoline-7-carbaldehyde 204 (2.5 g, 12.4 mmol) in dry THF (30 ml) at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 min. The mixture was quenched with sat. NH4Cl (10 ml) and the aqueous phase was extracted with EtOAc (20 ml). The organic phase was washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (50:50) as the eluent to give the title compound (3.39 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]#[N:11].S(=O)(=O)(O)[OH:21].O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[C:10]([NH2:11])=[O:21]
Reactant: N#CC(Nc1ccc(Cl)cc1)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)C(Nc1ccc(Cl)cc1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 Parts of 2,6-dichloro-α-[(4-chlorophenyl)amino]benzeneacetonitrile are added portionwise to 270 parts of sulfuric acid/water (10:1 by volume) and the whole is stirred overnight at room temperature. The reaction mixture is poured onto 2000 parts of ice-water. The precipitated product is filtered off, washed on the filter successively with water and 2-propanol and recrystallized from 560 parts of 2-propanol at -20° C., yielding 43.1 parts of 2,6-dichloro-α-[(4-chlorophenyl)amino]benzeneacetamide; mp. 178° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15](C)[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][CH:7]=1)=O.[CH2:26](I)C.CC(C)=O>O>[CH2:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2([CH3:26])[CH:18]=[CH:19][N:20]=[CH:21][CH2:22]2)=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCI
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCNc1ccc(NC(=O)NCC2(C)C=CN=CC2)cc1
Reaction time: 8 h

Procedure:
To 2.89 gms. (0.01 mole) of 1-(p-trifluoroacetamidophenyl)-3-methyl-3-(4-pyridylmethyl)urea [prepared by reacting 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea (Example 6., supra.) with trifluoroacetic anhydride (method of Hickenbottom, Reactions of Organic Compounds, Longmans, London, 1963)] there is added 6.24 gms. (0.04 mole) of ethyl iodide in 50 ml. of dry acetone. The acetone is then stripped and the residue added to 50 ml. of water. The aqueous mixture is warmed to reflux for about 30 minutes and then allowed to stand overnight. The mixture is then stripped of water to give 1-(p-ethylaminophenyl)-4-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].Cl>C(O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([O-:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
To 250 ml of an aqueous solution containing 73.5 g of phenol and 31.2 g of sodium hydroxide was added 50.0 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide, followed by reflux for 5 hours and then ice-cooling. To the ice-cooled reaction solution were successively added 50 ml of 36% hydrochloric acid and 200 ml of ethanol with stirring. The precipitate was collected by filtration, successively washed with water and ethanol, and air-dried to give 52.2 g of N-(5-nitro-2-phenoxyphenyl)methanesulfonamide as yellow prisms.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(OCC)C>CO.[Pd]>[CH3:27][N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]3[O:13][C:9]([C:5]4[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=4)=[CH:10][N:11]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: COc1cccc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)o2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CN1CCN(c2ccc(Nc3ncc(-c4cccc(O)c4)o3)cc2)CC1
Reaction time: 12 h
Yield: 101.5 %

Procedure:
To a stirred solution of the title compound of Example 4 (0.20 g, 0.45 mmol) in methanol (50 mL) was added palladium on carbon (10% w/w, 0.1 g) and was hydrogenated at 50 psi for 12 h. The catalyst was removed by filtration and the solvent was evaporated from the filtrate to leave a tan solid. Trituration with diethyl ether afforded a solid that was collected by filtration and dried under vacuum to leave the title compound (0.16 g, 96%). 1H NMR (400 MHz, d6-DMSO): δ 2.20 (s, 3H), 2.43 (m, 4H), 3.03 (m, 4H), 6.62 (d, J=9.16, 1H), 6.90 (m, 3H), 6.95 (d, J=7.69, 1H), 7.17 (t, J=7.87, 1H), 7.29 (s, 1H), 7.46 (d, J=8.61, 2H), 9.95 (s, 1H). MS (APCI, m/z)=336 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([O:26]CC)=O)[N:6]2C.[ClH:29].[NH2:30][C:31]([NH2:33])=[NH:32].[CH3:34][O-].[Na+]>CO>[ClH:1].[ClH:29].[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([N:32]=[C:31]([NH2:33])[NH:30][CH3:34])=[O:26])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CN(C)C)cc3)c2n1C
Reactant: N=C(N)N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(Cl)ccc(OCc3ccc(CN(C)C)cc3)c2[nH]1
Yield: 58.7 %

Procedure:
The reaction was carried out in a manner similar to Example 186 b) except for using 0.28 g (0.70 mmol) of ethyl 4-chloro-7-[4-(dimethylaminomethyl)-benzyloxy]-1-methyl-2-indolecarboxylate, 1.52 g (16.0 mmol) of guanidine hydrochloride, 0.86 g (16.0 mmol) of sodium methoxide and 40 ml of methanol. Thus, 0.10 g (29.3%) of 4-chloro-7-[4-(dimethylaminomethyl)-benzyloxy]-1-methyl-2-indoloylguanidine dihydrochloride was obtained.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]2[NH:37][N:36]=[CH:35][CH:34]=2)[CH:3]=1.IC.[C:40](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]2[CH:34]=[CH:35][N:36]([CH3:40])[N:37]=2)[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccn[nH]1)c(OCc1ccccc1)c2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1ccc(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.4 %

Procedure:
A solution of N-(4-fluoro-2-(1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.185 g, 0.36 mmol) in N,N-dimethylformamide (3 ml) was treated with iodomethane (0.025 ml, 0.4 mmol) and potassium carbonate (0.076 g, 0.55 mmol) and the resulting mixture was stirred at 25° C. for 5 h. The reaction mixture was then diluted with ethyl acetate, washed with water, brine, dried over anhydrous magnesium and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in dichloromethane) gave 0.120 g (64% yield) of the title compound as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.62 (6H, s, 2×CH3), 3.84 (3H, s, NCH3), 3.95–4.05 (4H, m, 2×CH2), 4.69 (2H, d, J=6.1 Hz, NCH2), 5.21 (2H, s, OCH2), 6.49 (1H, d, J=2.2 Hz, CH), 7.01 (1H, m, aromatic), 7.24–7.3 (4H, m, aromatics), 7.40 (1H, d, J=2.2 Hz, CH), 7.42–7.45 (2H, m, aromatics), 7.64 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.75 (1H, broad t, NH). HRMS (ESI+) calculated for C28H29FN5O4 [M+H+]: 518.2204. found: 518.2222.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[N:41]([CH:43]=[CH:44][N:45]=2)[N:42]=1>O>[N:45]1[CH:44]=[CH:43][N:41]2[C:40]=1[CH:39]=[CH:38][C:37]([CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]3[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:6][CH:7]=1)=[N:42]2
Reactant: ClCc1ccc2nccn2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5nccn5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (1.2 g, 3.8 mmol) was added to a mixture of cesium carbonate (3.7 g, 11.6 mmol) and DMF (25 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-(chloromethyl) imidazo[1,2-b]pyridazine (0.96 g, 5 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.8 g, 47%) as Off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.2 (d, 1H), 7.8 (s, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.3 (s, 2H), 3.9 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=442.1. HPLC: (95.8%, Condition-A).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15]
Reactant: CCCOC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 38.1 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.493 g, 1.5 mmol) and 4-propoxypiperidine (0.430 g, 3.0 mmol) in MeCN (2 mL) and shaken at 60° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH48) (0.197 g, 38%). 1H NMR (CD3OD) d 7.26-7.19 (m, 3H), 7.03-6.98 (m, 1H), 3.96 (d, J=7.0 Hz, 2H), 3.40 (t, J=6.7 Hz, 2H), 2.90-2.86 (m, 2H), 2.74-2.71 (m, 1H), 2.65-2.54 (m, 3H), 2.26-1.99 (m, 6H), 1.87-1.84 (m, 2H), 1.59-1.49 (m, 4H), 0.91 (t, J=7.4 Hz, CH3), 0.85 (d, J=6.6 Hz, CH3); 13C NMR (CD3OD) d 173.0, 140.3, 129.1, 128.4, 128.4, 124.3, 116.8, 76.3, 70.7, 64.5, 53.2, 52.8, 32.9, 32.4, 32.4, 30.3, 26.2, 24.3, 17.1, 11.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:28][CH3:29])[CH:20]=1>>[ClH:1].[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH:23][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(OC)cc1Cl
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.290 mmol) similar to Example 117 and isolated as a brown solid (52 mg, 63%). 1H NMR (CDCl3): 9.66–9.64 (m, 1H), 8.76–8.71 (m, 2H), 8.35 (s, 1H), 7.54 (s, 1H), 7.45–7.41 (m, 1H), 7.01 (s, 1H), 6.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[NH:7]2.[NH:27]1[C:35]2[C:30](=CC=C[CH:34]=2)[C@@:29]2([C:47]3[C:38](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCCOCCOC>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[N:7]2[CH2:34][C:35]1[CH:30]=[CH:29][CH:47]=[CH:38][N:27]=1
Reactant: COc1cc2c(c(OC)c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: COCCOCCBr
Product: COc1cc(OC)c2c(c1)N(Cc1ccccn1)C(=O)C21COc2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 1-bromo-2-(2-methoxyethoxy)ethane, 4′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp 187-188° C.; 1H NMR (300 MHz, DMSO-d6) δ8.59-8.34 (m, 1H), 7.86-7.66 (m, 1H), 7.44-7.19 (m, 2H), 6.51-6.32 (m, 1H), 6.32-6.14 (m, 3H), 5.17-4.80 (m, 2H), 4.79-4.50 (m, 2H), 4.25-3.95 (m, 4H), 3.66 (s, 3H), 3.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.7, 162.0, 156.7, 155.8, 155.6, 149.4, 144.3, 144.2, 137.7, 137.1, 122.7, 121.5, 120.3, 111.1, 108.9, 98.9, 93.1, 89.5, 64.5, 63.9, 57.1, 55.6, 46.2; MS (ES+) m/z 447.1 (M+1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[CH2:23]2)=[C:15]([S:30][NH2:31])[N:14]=1>C(O)C>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[CH2:23]2)=[C:15]([S:30]([NH2:31])=[O:6])[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
A solution of m-chloroperoxybenzoic acid (0.50 g, 2.5 mmol) in ethanol (50 mL) was added dropwise to an ice-cooled (0°-5° C.), stirred solution of 45 (0.75 g, 2.5 mmol) in ethanol (150 mL), during 15 min. The reaction mixture was allowed to stand at room temperature overnight and the crystalline product that deposited was collected by filtration. The product was washed with ethanol (2×15 mL) and air-dried to yield 0.24 g (31%) of 46. mp 178° C. (dec.). IR (KBr): 1040, 1300 (s, S=O), 3100-3600 (NH2, OH)cm-1 ; UV: λmax (pH 1) 329 nm (ε 3,800): λmax (pH 7) 323 nm (ε 5,800): λmax (pH 11) 323 nm (ε 3,700): 1H NMR (DMSO-d6): δ 6.27 (dd, 1, J=5.5 Hz, C1'H), 6.50 (s, 2, SONH2, exchanged with D2O), 6.94 (s, 2, NH2, exchanged with D2O), 8.43 (s, 1, C8H), and other sugar protons. Anal. Calcd. for C10H14N6O4S (314.32): C, 38.21; H, 4.49; N, 26.74; S, 10.20. Found: C, 38.34; H, 4.59; N, 26.47; S, 10.17.