Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][CH2:17][S:18][CH3:19].[I-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][S:18][CH3:19])=[CH:4][CH:3]=1
Reactant: CSCCCl
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCOc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In DMF (120 ml) was dissolved 4-bromophenol (15 g). To the mixture was added at room temperature potassium carbonate (21.6 g) and then were added 2-chloroethylmethylsulfide (10 ml) and sodium iodide (15.6 g), and the mixture was stirred at 90° C. for 16 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(2-methylthioethoxy)benzene (4.0 g). In THF (58 ml) was dissolved 1-bromo-4-(2-methylthioethoxy)benzene (3.9 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (10 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (4.6 g) in THF (9.3 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (20 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(2-methylthioethoxy)phenyl borate (1.39 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[C:24]1([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C@@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](COc2ccccc2CCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CCc2ccccc2OC[C@H]2CNCCO2)cc1
Reaction time: 1 h
Yield: 89 %

Procedure:
0.930 g of (R)-4-t-butoxycarbonyl-2-[2-(2-phenylethyl)phenoxymethyl]morpholine [prepared as described in step (a) above] was dissolved in 5 ml of dioxane, and 5 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution, which was then allowed to stand at room temperature for 1 hour. At the end of this time, the mixture was concentrated by distillation under reduced pressure, and the resulting oil was dissolved in 25 ml of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 0.692 g (yield 89%) of the title compound as colorless crystals, melting at 150°-151° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)(O)[CH2:6][CH3:7].Cl>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:5](=[CH:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:18])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: Cl
Product: CC=C(c1cccc(OC)c1)[C@@H](C)CN(C)C

Procedure:
WO2008012047 describes yet another method for the preparation of tapentadol, wherein 1-(3-methoxyphenyl)propan-1-one is reacted with dimethyl amine hydrochloride and paraformaldehyde under Mannich reaction condition to get 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one hydrochloride, which after reacting with sodium hydroxide is reacted with (2R,3R)—O,O′-dibenzoyl tartaric acid monohydrate to get (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one L-(−)-dibenzoyltartarate. The dibenzoyl tartrate salt is further reacted with diethyl amine to isolate keto compound (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one. The keto compound is reacted with ethyl magnesium halide under Grignard condition to isolate the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The hydrochloride salt of the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol on reaction with aqueous hydrochloric acid undergoes dehydration yielding the compound (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine, which after hydrogenation using homogeneous or heterogeneous catalyst results in the mixture of compound (2R,3R))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine having Z:E ratio of 5.5:1. The required compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine is separated from the mixture by making hydrochloride salt. The isolated salt is dissolved in methane sulphonic acid and treated with methionine to get the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I, which is isolated as hydrochloride salt of tapentadol hydrochloride.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][O:3][CH2:4][C:5]([O-:7])=[O:6].BrCCl.[CH2:15]([Cl:17])[Cl:16]>>[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][O:3][CH2:4][C:5]([O:7][CH:15]([Cl:17])[Cl:16])=[O:6]
Reactant: ClCCl
Reactant: CCOC(=O)COCC(=O)[O-]
Agent: ClCBr
Product: CCOC(=O)COCC(=O)OC(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of the tetrabutylammonium salt of monoethyl diglycolate (16 g, 0.04 mol) in methylene chloride (125 ml) was added to bromochloromethane (200 ml) over 1.5 hr. The resulting solution was stirred at room temperature overnight and then evaporated to dryness. The residue was chromatographed on silica eluting with ethyl acetate/hexane, 40/60 and the fractions containing product combined and evaporated to give ethyl dichloromethyl diglycolate (0.836 g, 10%) as a colorless oil. NMR analysis showed the material to be approximately 70% pure, but was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][NH:23][CH2:24]2)=[CH:19][CH:18]=1.CN1CCOCC1.O>CN1CCCC1=O>[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23]([C:2]3[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]4)[N:5]=[C:4]([NH2:15])[N:3]=3)[CH2:24]2)=[CH:19][CH:18]=1
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (500.0 mg, 2.196 mmol), 7-bromo-1,2,3,4-tetrahydroisoquinoline (512.3 mg, 2.416 mmol, Alfa Aesar, Cat. No. B25712) and 4-methylmorpholine (289.7 μL, 2.635 mmol) in N-methylpyrrolidinone (10 mL) was heated at 180° C. overnight. The reaction mixture was cooled to r.t., poured into water, extracted with AcOEt, washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by flash chromatograph on a silica gel column using 10% MeOH in CH2Cl2 (include 1% NH3) as eluent to afford the desired compound 695 mg (yield 78.5%). LCMS (M+H)+: m/z=403.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Br:7].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:31][CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:31][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[O:10])[S:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cc(Br)c(Br)s1
Yield: 71.8 %

Procedure:
To a solution of 2.55 g (8.91 mmol) of 4,5-dibromothiophene-2-carboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 2.79 g of the desired compound (yield: 71.8%, colorless powder). mp: 129.0°-130.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1.[CH2:21]([OH:24])[CH2:22][CH3:23]>>[CH2:21]([O:24][C:17](=[O:18])[CH2:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][CH:13]=1)[CH3:20])[CH2:22][CH3:23]
Reactant: CCCO
Reactant: CC(CC(=O)Cl)c1ccc(-c2ccc(F)cc2F)cc1
Product: CCCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of crude 3-(2',4'-difluoro-4-biphenylyl)-butyryl chloride and 10 ml. of n-propanol are warmed to 95° for 3 hours and the mixture is evaporated and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid n-propyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O.[Cu]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH3:14])[CH:7]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Oc3ccc(F)cc3)c2)cc1
Temperature: 190 °C
Yield: 91.1 %

Procedure:
The mixture of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (3) (2.0 g, 5.54 mmole), 4-fluorophenol (3.1 g, 27.7 mmole), copper oxide (0.5 g, catalyst) and cesium carbonate (5.4 g, 16.6 mmole) in 10 mL of 1-N-methyl-2-pyrrolidinone is heated to 190° C. in a microwave reactor for 30 minutes. The reaction solution is diluted with 150 mL of EtOAc and filtered through celite. The filtrate is washed with 4×30 mL of water. The organic layer is concentrated and purified by flash column chromatography (hexane 100% to hexane 60% and EtOAc 40% by gradient in 20 minutes)) to give 3-(4-fluoro-phenoxy)-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (4) (1.98 g, yield 91%) as a light yellow viscose liquid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.[OH-].[Na+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:2]1([CH:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:18]2[CH2:19][CH2:20][C@H:16]([OH:15])[CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CCNC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
Benzophenone (5.47 g) was dissolved in tetrahydrofuran under an argon atmosphere. Titanium(IV) tetraisopropoxide (13.3 mL) was added to the solution at room temperature. After 0.25 h, (3S)-3-hydroxypyrrolidine (2.61 g) in tetrahydrofuran (5.5 mL) was added dropwise to the mixture, and the resultant mixture was stirred at room temperature for 1 hour. After 1 h, polymethylhydrosiloxane (5.8 mL) was added to the reaction mixture, and the resultant mixture was stirred. After 19 h, a 28 wt. % aqueous sodium hydroxide solution (60 mL) was added to the reaction mixture, and the resultant mixture was refluxed for 0.5 hour. The temperature of the reaction mixture was lowered to room temperature and then extracted with toluene. The formed aqueous layer was again extracted with toluene, and the organic layers were combined together, washed with saturated brine, and then dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystalline residue. The residue was subjected to silica gel chromatography, to thereby give the target compound (4.65 g, yield 61.2%). The target compound was purified through recrystallization from isopropyl alcohol.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:5]([CH2:4][C:2](=[CH2:3])[C:1]([OH:8])=[O:7])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: C=C(CC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of itaconic anhydride (33.6 g, 0.3 mol) in 100 ml of toluene is added benzyl alcohol (32.4 g, 0.3 mol). The resulting solution is heated to reflux for 3 hours. After cooling down to room temperature, hexanes (100 mL) are added to the above mixture and are continued to stir for 8 hours. A white solid is collected by filtration and washed with hexanes and dried in vacuum, giving rise to 55 g (83% yield) of the desired product: 2-(benzyloxycarbonylmethyl)acrylic acid monomer.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][S:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.[N:25]1([CH2:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)O)[CH:29]=[CH:28][N:27]=[CH:26]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:25]1([CH2:30][C@@H:31]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: COC(=O)c1ccc(SCc2c(O)ccc3c2CCCC3=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 99 %

Procedure:
Using method in Example 154, this compound was prepared from methyl 4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate (1.81 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3 mmol), Ph3P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g, 8.0 mmol) and purified by a silica-column (eluting with dichloromethane-MeOH 20:1) as a solid-foam, 2.70 g, 99% yield; mp 75° C. NMR spectrum was consistent with structure. Calcd. For C30H28N2O4S.H2O:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(Oc2ccccc2)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(Oc2ccccc2)c1
Temperature: 60 °C
Yield: 98.5 %

Procedure:
200 g (1.025 mols) of 3-phenoxybenzonitrile is placed together with 1 liter of methanol, 200 g of liquid ammonia and 50 g of Raney nickel into a steel autoclave. This is then heated to 60° C., and stirring is maintained for one hour with an initial hydrogen pressure of 120 bars. After removal of the mixture from the autoclave, the catalyst is filtered off, the solvent is distilled off at normal pressure, and the residue is distilled in an oil-pump vacuum to obtain 200.3 g (1.01 mols) of 3-phenoxybenzylamine (98.7% strength), corresponding to a yield of 94.7% of theory; b.p. 94° C./3 Pa; nD20 =1.5946.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([O-])=O.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]([N:20]=[N+:21]=[N-:22])=[O:19])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=NC(=O)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-benzyl-3-(4-hydrazinocarbonyl-1,2,3-triazol -1-yl)pyrrolidine (3.6 g, 0.0125 mol) was dissolved in hot water (40 ml) and then cooled to 0° C. To the cooled suspension NaNO2 (950 mg, 0.0137 mol in 3 ml of water) was added dropwise and then glacial AcOH (7 ml) was added to the reaction mixture was stirred at 0° C. for 15 min. Reaction mixture was then neutralized by the addition of saturated NaHCO3. The separated white solid was filtered and washed with water, dried in vacuum oven. Yield: 3.73 g (100%), m.p. 160° C. 1H NMR (CDCl3) δ: 1.95-2.15 (m, 1H), 2.37-2.83 (m, 3H), 2.94-3.22 (m, 2H), 3.70 (d, 2H), 5.75-5.87 (m, 1H), 7.30 (s, 5H), 8.47 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:43][C:44]1[CH:45]=[C:46]([O:59][CH3:60])[CH:47]=[C:48]2[C:53]=1[O:52][C:51]([C:54]([O:56][CH3:57])=[O:55])=[CH:50][C:49]2=[O:58]>ClCCl>[CH3:60][O:59][C:46]1[CH:47]=[C:48]2[C:53](=[C:44]([NH:43][C:19]([CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([O:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:11][CH2:12]3)=[O:20])[CH:45]=1)[O:52][C:51]([C:54]([O:56][CH3:57])=[O:55])=[CH:50][C:49]2=[O:58]
Reactant: COC(=O)c1cc(=O)c2cc(OC)cc(N)c2o1
Reactant: O=C(O)CCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1cc(=O)c2cc(OC)cc(NC(=O)CCCN3CCC(OC(c4ccc(Cl)cc4)c4ccccn4)CC3)c2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
To 2.0 g (5.14 mmol) of 4-(4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidinyl)butanoic acid dissolved in 20 ml of dichloromethane was added 1.27 g (6.17 mmol) of dicyclohexylcarbodiimide, and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was added 1.54 g (6.18 mmol) of 8-amino-6-methoxy-2-methoxycarbonylchromone, and the mixture was further stirred at 0° C. for 3 hours. The reaction mixture was allowed to stand at room temperature overnight and then concentrated under reduced pressure. To the residue was added ethyl acetate, and the insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography using a mixed solvent of chloroform and methanol in a volume ratio of 20:1 as an eluent to obtain 0.50 g (yield: 17%) of 1-(3-[N-(6-methoxy-2-methoxycarbonylchromon-8-yl)carbamoyl]propyl)-4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine as a brown foamy product.
Reaction SMILES: C(OC(=O)[C:5](Cl)([F:7])[F:6])C.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:6][CH:5]([F:7])[O:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(OC(F)F)cc5n4)CC3)cc2N1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Chloro-difluoro-acetic acid ethyl ester (13.8 μL, 0.10 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (50 mg, 0.10 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by potassium carbonate (14.4 mg, 0.10 mmol, 1.0 eq). After 15 hours stirring at 70° C., solvent is evaporated and the residue is acidified with 1N hydrochloric acid aqueous solution and the resulting aqueous layer is extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-difluoromethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as a white lyophilizated powder (5 mg, 10% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Reactant: OB(O)c1cccnc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1-c1cccnc1
Temperature: 90 °C

Procedure:
A sealable vial was charged with N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (27.0 mg, 42.5 μmol), 3-pyridylboronic acid (6.27 mg, 51.0 μmol), and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (2.36 mg, 4.25 μmol). The vial was sealed and 1,4-dioxane (1 mL) was added under positive N2 flow. Then an aqueous solution of sodium carbonate (1.9 M, 89.5 μl, 170 μmol) was added via syringe. The resulting solution was sparged with N2 for 10 minutes, then heated at 90° C. for 18 h. The solution was cooled to rt and directly absorbed onto a 5 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford the title compound N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide as a yellow solid. LCMS (ESI positive ionization) m/z: 586 (M+1); 1H NMR (400 MHz, MeOH) δ ppm 2.18 (s, 3H); 6.81 (t, J=73.11 Hz, 1H); 7.32-7.40 (m, 1H); 7.48 (t, J=8.02 Hz, 1H); 7.53-7.57 (m, 1H); 7.58-7.63 (m, 1H); 7.67 (dd, J=7.87, 5.04 Hz, 1H); 7.90 (d, J=9.49 Hz, 1H); 8.15 (d, J=9.49 Hz, 1H); 8.47 (d, J=8.02 Hz, 1H); 8.60 (d, J=3.52 Hz, 1H); 8.64 (d, J=2.25 Hz, 1H); 8.77 (d, J=2.25 Hz, 1H); 8.97 (s, 1H).