Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10](Cl)=[O:11].[CH:14]([OH:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10]([O:17][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: CC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CC(C)O
Solvent: c1ccccc1
Product: CC(=O)/C=C/[C@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 6 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride and 2.7 ml of isopropanol were reacted to obtain 1.96 g of isopropyl (1R,cis) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-39°±5° (c=0.2% in benzene).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Li])[CH2:26][CH2:27][CH3:28]>O1CCCC1.CCCCCC>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:25][CH2:26][CH2:27][CH3:28])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1c(SCc2ccc(C(C)(C)C)cc2)cnn(C(C)(C)C)c1=O
Temperature: 0 °C

Procedure:
To a solution of 0.73 g (0.002 mol) of the 2-t-butyl-5-(p-t-butylbenzylthio)-4-chloro-3(2H)-pyridazinone thus obtained dissolved in 20 ml of tetrahydrofuran was added 3.0 ml of a solution of 10% butyl lithium dissolved in hexane at -70° C. under stirring. The reaction temperature was gradually raised from -70° C. to room temperature, and then the reaction mixture was stirred at room temperature for one hour. The reaction mixture was poured into 50 ml of ice water and extracted with 50 ml of chloroform. The resulting chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate and freed of solvent by distillation to give 0.65 g of a crude product. The crude product was purified by preparative thin layer chromatography on silica gel (developer:benzene) to obtain 0.38 g of 2-t-butyl-4-butyl-5-(p-t-butylbenzylthio)-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([NH2:14])=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([NH2:14])=[O:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(N)=O)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Yield: 51.9 %

Procedure:
Methyl 3-bromo-4-(aminocarbonyl)benzoate (0.54 mmol) was dissolved in methanol (1 mL) and was treated with 1M aqueous sodium hydroxide (1 mL) at 45° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to afford an aqueous residue that was acidified with 1N aqueous hydrochloric acid to pH ˜3. The precipitate was collected by filtration, washed with water, and dried to afford 3-bromo-4-(aminocarbonyl)benzoic acid (69.4 mg, 0.28 mmol, 53% overall). 1H NMR (400 MHz, d6-DMSO): 13.47 (br s, 1H), 8.08 (dd, 1H), 8.00 (br s, 1H), 7.94 (dd, 1H), 7.73 (br s, 1H), 7.51 (d, 1H); MS (EI) for C8H6BrNO3: 242, 244(M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[CH2:9][CH2:10]2)=[CH:5][CH:4]=1.Cl>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH2:9][CH2:10]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1[N+](=O)[O-])=C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Temperature: 25 °C
Reaction time: 25 h
Yield: 70.3 %

Procedure:
To a solution of 7-methoxy-3-(2-nitrophenyl)-1,2-dihydronaphthalene (1.5 g) in tetrahydrofuran (10 ml) and methanol (10 ml) were sequentially added 10% palladium-activated charcoal (300 mg) and concentrated hydrochloric acid (0.8 ml), and the solution was stirred for 25 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solution was neutralized with ammonia solution, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (949 mg).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[CH3:7]>C(#N)C>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:6](=[O:8])[CH:7]=[CH:2][C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccco1
Solvent: CC#N
Product: O=C(O)C=CC(=O)c1ccco1
Yield: 21.7 %

Procedure:
A mixture of 14.8 g of glyoxylic acid (in 18.5 cc of water) and 22 g of 2-acetylfuran is heated at 125°-135° C. for about 5 hours; the water is removed as it forms via a Dean Stark tube. The mass cyrstallizes over about a 16 hour period and is dissolved in 600 cc of ethyl acetate and extracted into 600 cc of 10% sodium carbonate. The aqueous solution is treated with activated charcoal and a filter aid, and then filtered. It is made strongly acid with 20% HCl and the solid which precipitates is extracted with ethyl acetate. The ethyl acetate is dried over MgSO4 and removed to yield a solid residue which is dissolved in 100 cc hot acetonitrile and allowed to cool for about 16 hours. The solid is filtered to yield 7.2 g of the title compound, melting point 153°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)CC(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:8][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To 4-amino-2-fluorophenol (see Step A of Example 19, 127 mg, 1.0 mmol) in DMF (5 mL) at rt under nitrogen was added sodium hydride (80 mg, 2 mmol, 60%). After stirring at rt for 10 min, 4-chloro-3-nitropyridine hydrochloride (Lancaster, 195 mg, 1.0 mmol) was added. The mixture was stirred at rt for 1 h and was then diluted with EtOAc (50 mL) and washed with water, 10% aqueous lithium chloride solution, and then brine (1×30 mL each). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc to give the title compound (150 mg, 60%) as a yellow-orange solid. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.63 (d, 1H, J=6 Hz), 7.09 (t, 1H, J=9.2 Hz), 6.92 (d, 1H, J=6 Hz), 6.55 (dd, 1H, J=13.2, 2.4 Hz), 6.45 (dd, 1H, J=9.2, 2.4 Hz), 5.61 (s, 2H); MS(ESI+) m/z 250.18 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][N:17]([CH3:21])[C:18]([N:3]1[CH:4]([CH3:8])[CH2:5][NH:6][CH2:7][CH:2]1[CH3:1])=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC1CNCC(C)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CNCC(C)N1C(=O)N(C)C
Temperature: 0 °C
Yield: 69.7 %

Procedure:
To an ice-cold solution of 2,6-dimethyl piperazine (179 mmol, 20.4 g), methylene chloride (200 mL), and triethylamine (214 mmol, 29.9 mL) was added dropwise dimethylcarbamoyl chloride (179 mmol, 16.4 mL). After 4 hr the reaction was quenched with a saturated sodium bicarbonate solution and the methylene chloride layer was collected, dried, filtered and the filtrate was evaporated to dryness to obtain an orange oil, 2,6-dimethyl-piperazine-1-carboxylic acid dimethylamide (70%, 23.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1ccc(Cl)nc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
3.99 g (20.0 mmol) of the compound from Example 1A are dissolved in 13.7 ml of dimethylformamide diethyl acetal, and the mixture is stirred with microwave irradiation at 90° C. for 30 min. The mixture is then concentrated on a rotary evaporator, and the residue is chromatographed on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol 20:1).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:25])([CH3:3])[CH3:2].I[CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]3)[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C(C)C
Temperature: 80 °C
Yield: 32.5 %

Procedure:
To a solution of 1-isopropyl-5-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydroquinoline-3-carboxamide (300 mg, 0.88 mmol, step 4 in preparation 3) in N,N-dimethylformamide (30 mL), tert-butyl 4-(iodomethyl)piperidine-1-caroxylate (343 mg, 1.05 mmol, Villalobos Anabella et al., J. Med. Chem., 1994, 37, 2721) and potassium carbonate (610 mg, 4.4 mmol) were added at room temperature. The mixture was heated at 80° C. overnight. After cooled to room temperature, water (30 mL) was added and extracted with diethyl ether (50 mL×2). The combined organic layer was washed with water (20 mL×2), brine (20 mL), dried over magnesium sulfate and concentrated in vacuo gave yellow oil, which was chromatographed on a column of silica gel eluting with ethyl 25% ammonium oxide/methanol/dichloromethane (3:30:1000) to give 154 mg (32%) of the title compound as a clear colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:13])[CH:8]=[CH:7][N:6]=1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)(O)[O-].[Na+]>CS(C)=O.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=1)[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=1
Reactant: COC(=O)CBr
Reactant: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(SC)n1
Reaction time: 0.5 h

Procedure:
Sodium hydride (95%, 1.78 g, 83 mmol) and dimethyl sulfoxide (DMSO) (150 mL) were combined under argon in a 3-neck 1L round bottom flask. A solution of Compound 3 in DMSO (50 mL) was added dropwise over 0.75 h using an addition funnel. After stirring an additional 0.5 h, methyl bromoacetate (7.9 mL, 83 mmol) in DMSO (50 mL) was added dropwise. After 18 h, the contents of the reaction flask were poured into water. Saturated sodium bicarbonate was added and the resulting solution was extracted several times with ethyl acetate. The combined organic extracts were washed successively with water and brine. The organic layer was dried with anhydrous sodium sulfate then concentrated in vacuo to give an oil. Purification by flash column chromatography (hexane:ethyl acetate 70:30) afforded Compound 4 as an oil: 24.6 g (64 mmol, 100%)
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.67 g (47%); off white powder; mp 203° C.; MS: 418.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrBr
Reactant: O=Cc1ccc(O)cc1F
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(O)cc1F
Temperature: 45 °C
Reaction time: 26 h
Yield: 81.2 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzaldehyde (2.16 g, 15.4 mmol) in acetic acid (70 mL) was added a solution of bromine (2.71 g, 17.0 mmol) in acetic acid (10 mL), and the mixture was stirred at 45° C. for 26 hr. The reaction mixture was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (2.74 g, yield 81%) as colorless crystals.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1)C.BrN1C(=O)CCC1=O.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[NH2:31]>O1CCOCC1.O>[CH3:13][S:12][C:8]1[N:7]=[C:6]([C:5]2[N:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([O:23][CH3:22])=[O:32])[C:26]3=[N:31][CH:4]=2)[CH:11]=[CH:10][N:9]=1
Reactant: COC(=O)c1cccnc1N
Reactant: CCO/C=C/c1ccnc(SC)n1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccn2c(-c3ccnc(SC)n3)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
137.2 mg of the 4-[(E)-2-ethoxyvinyl]-2-(methylthio)pyrimidine [25-2] was dissolved in a mixture solvent of 5 mL of 1,4-dioxane and 2 mL of water, and 124.1 mg of N-bromosuccinimide was added thereto. After stirring at room temperature for 1 hour, 106 mg of the 2-aminonicotinic acid methylester [25-1] was added, and stirred at 85° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography, to obtain 106.1 mg of methyl 3-[2-(methylthio)-4-pyrimidinyl]imidazo[1,2-a]pyridine-8-carboxylate [25-3].
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])#[N:8].Br[C:20]1[N:24]2[N:25]=[C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>O1CCOCC1.O>[F:41][C:35]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:34]=1[CH:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([C:12]3[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[C:10]([F:18])[CH:11]=3)=[CH:21][N:22]=2)[N:25]=1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cnc3ccc(N4CCCC4c4cc(F)ccc4F)nn23)cc1F
Temperature: 150 °C

Procedure:
In step 12-1, [Pd(Dppf)2]Cl2 (90 mg, 0.11 mmol), sodium carbonate (0.41 g, 3.9 mmol), and 4-cyano-3-fluorophenylboronic acid (0.36 g, 2.2 mmol) were added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (0.42 g, 1.1 mmol) in 3 mL of dioxane and 1 mL of DI water. The reaction mixture was heated in a microwave for twenty minutes at 150° C., and the slurry was then cooled to room temperature and filtered through a 0.2 μM nylon fit. The solvent was removed from the mother liquor and the remaining residue was reconstituted in dichloromethane (DCM). This solution was loaded onto a 12 g silica gel column and eluted using a 0-10% methanol in DCM gradient over 30 minutes. The solvent was removed from the desired fractions to yield 4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzonitrile. m/z=420.2 [M+1].
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([O:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: OCCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
Triethylamine (691 mL, 4.96 mol) was added to an ice cold solution of 1-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in dichloromethane (2.2 L). Acetyl chloride (282 mL, 3.97 mol) was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes with ice-bath cooling. The reaction mixture was washed sequentially with water (2×1 L), 1N HCl (1 L, 500 mL), water (1 L), 5% aqueous NaHCO3 (500 mL), water (1 L), and brine (500 mL), then dried over magnesium sulfate, filtered, and evaporated to afford 1-(2-acetoxy-ethyl)-naphthalene (723.2 g) as a yellow oil that slowly crystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: O=S(=O)(O)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
1,800 ml of chlorosulphonic acid is placed in a 4 liter flask fitted with an agitator and a thermometer, and is cooled to 10° C. 328 g of finely powdered 2,4-dimethoxy benzoic acid is added in stages in the course of 45 minutes, between 10° and 15° C. The acid dissolves gradually as it is introduced. When all the acid has been added the solution is gradually heated to 55° C. and that temperature is maintained for 5 hours. The solution is left to stand overnight, then poured little by little into 17 kg of ice, with agitation and with external cooling. The acid which is precipitated is drained, washed with water and dried in air.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(F)cc1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(4-fluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.60-8.53 (m, 1H), 8.42-8.35 (m, 1H), 8.15-8.07 (m, 1H), 8.05-7.95 (m, 3H), 7.84-7.76 (m, 1H), 7.72-7.66 (m, 2H), 7.35-7.29 (m, 2H), 7.17 (t, J=8.9, 2H), 3.67 (s, 2H); MS (APCI+) M/Z 438 (M+H)+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.Cl>[OH-].[K+].O>[CH:4]1[CH:2]=[C:2]2[CH:4]=[C:6]3[C:11](=[N:1][C:8]2=[CH:7][CH:6]=1)[CH:10]=[CH:9][CH:8]=[CH:7]3
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2nc3ccccc3cc2c1
Temperature: 0 °C

Procedure:
The isatin product was refluxed in 110 mL of 10% KOH solution in water over night. The dark green mixture was cooled and acidified with 400 mL of 1:1 ice/5 M HCl. The solid was washed with water and air-dried yielding the acridine acid. 1H NMR (DMSO-d6) δ7.81-7.94 (m, 4H), 8.31-8.36 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@H:12]([O:13][S:21]([CH3:20])(=[O:23])=[O:22])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6]
Reactant: CO[C@H]1O[C@@H]2[C@@H](OC[C@H]2O)[C@@H]1OC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OS(C)(=O)=O)[C@@H]1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Methyl 3,6-anhydro-2-O-methyl-α-D-idofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at 0° C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-L-glucofuranoside as a colorless oil, 669 mg, 95% yield, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:33])[NH:6]2.[OH-].[Na+]>CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:33])[NH:6]2
Reactant: COC(=O)C1(COc2cc3nccc(Oc4ccc5[nH]c(C)cc5c4F)c3cc2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(C(=O)O)CC1
Yield: 51.6 %

Procedure:
The product of Example 9 (300 mg) was mixed with 15% NaOH (3 eq) in MeOH (15 ml) and refluxed for 30 minutes. The reaction was evaporated and adjusted to PH=6, then filtered to give the titled compound (150 mg). Mass: (M+1), 437
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1)[S:3]([NH:6]C(=O)OC(C)(C)C)(=[O:5])=[O:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:1][N:2]([CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1)[S:3]([NH2:6])(=[O:5])=[O:4]
Reactant: CN(C1CCOC1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C1CCOC1)S(N)(=O)=O

Procedure:
tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate (1.47 g, 5.23 mmol) was dissolved in 70 mL of CH2Cl2 and 45 mL of trifluoroacetic acid. After 1 h the solution was concentrated in vacuo, diluted in CH2Cl2, washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The solution was concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, DMSO-d6) δ 4.25-4.31 (m, 1H); 3.79-3.84 (m, 1H); 3.58-3.66 (m, 2H); 3.47-3.52 (m, 1H); 2.56 (s, 3H), 2.04-2.10 (m, 1H); 1.81-1.88 (m, 1H).