Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]2[C:21]=1[C:20](=[O:22])[CH2:19][CH2:18]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:23][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: COc1ccc(O)c2c1C(=O)CC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OCC)Oc1ccc(OC)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-methoxy-4-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product, O-ethyl S-propyl O-(7-methoxyindan-1-on-4-yl) thiophosphate.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([F:27])[CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:37]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([F:27])[CH:13]=2)=[O:8])=[CH:29][CH:30]=1)(=[S:37])[NH2:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1F
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1F

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (504 mg), pyridine (35 ml), triethylamine (5 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-2-fluorophenoxyacetate (509 mg): m/Z 447 (M)+. ; 460 (M+Na)+.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[Li].[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13].CCOCC>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:1]([C:9]1[C:8]([CH3:13])=[C:7]([Cl:6])[CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3]
Reactant: Cc1cnccc1Cl
Reactant: CCCI
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCc1nccc(Cl)c1C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of propyl iodide (12.7 g) in THF (10 ml) is added lithium (0.45 g) and the reaction is allowed to stir at room temperature until complete dissolution of the lithium. 4-Chloro-3-methyl-pyridine (9.5 g) is then added and the mixture allowed to stir at 40° C. for 4 hours. After cooling at room temperature, ether is added and the organic phase washed with water. After removal of the solvent the desired product is obtained by chromatography using hexane/ether 9/1 as solvent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=[O:14])[CH2:9][C:8]1=[O:20])#[N:2].[C:24](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:14])[CH3:24])[CH2:9][C:8]1=[O:20])#[N:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(3-cyanobenzyl)-4-Boc-2-piperazinone (2.5 g, 7.9 mmol) in CH2Cl2 (20 mL) at 0° C. was added TFA (10 mL). The mixture was stirred at 0° C. for 2 h, then the solvents were removed in vacuo. The crude 1-(3-cyanobenzyl)-2-piperazinone TFA salt was partitioned between EtOAc (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). To the stirred two-phase mixture was added acetic anhydride (1.5 mL, 15 mmol) dropwise over a period of 5 min. The mixture was stirred at ambient temperature for 16 h. The EtOAc layer was separated, dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified on a silica gel column using a gradient mobile phase of 2%, 3%, 4% MeOH in CH2Cl2. 1-(3-cyanobenzyl)-4-acetyl-2-piperazinone was obtained as a solid.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH2:9][CH2:10][OH:11])C.[Cl:12][C:13]1C=NC=[CH:17][CH:18]=1.CN(C=O)C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[Cl:12][C:13]1[C:9]([CH:10]=[O:11])=[N:7][CH:6]=[CH:17][CH:18]=1
Reactant: CN(C)CCO
Reactant: Clc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium (96 ml, 240 ml) in n-hexane was added to a solution of N,N dimethylaminoethanol (10.65 g, 120 mmol) in abs. THF (70 ml) at −5° C. under argon within 25 min. The reaction mixture was stirred for 30 min at 0° C. and cooled down to −70° C. At a temperature of −70 to −65° C., a solution of 3-chloropyridine (3.8 ml, 4.5 g, 40 mmol) in abs. THF (60 ml) was added within 10 min and stirred for a further hour at this temperature. Abs. DMF (12.3 ml, 11.7 g, 160 mmol) in THF (100 ml) was then added within 15 min at −65 to −60° C. The dark brown solution was heated within 1 h to 10° C. At a temperature of −20 to −10° C., the reaction mixture was hydrolysed with sat. ammonium chloride solution (120 ml). The mixture was then stirred for 30 min at 0° C. The phases were not separated. The organic solvents were removed under vacuum. The residue was extracted with DCM (120 ml). The phases were separated. The aqueous phase was extracted with DCM (3×120 ml). The organic phases were combined and concentrated without drying. The residue was a brown oil which was further purified by adding water (4×50 ml) and decanting. After the addition of DCM (250 ml) and sodium sulphate, the mixture was dried overnight and then concentrated. The crude product of the 3-chloropyridine-2-carbaldehyde (F) was obtained as a hydrate (brown oil 8.73 g, theoretical yield 6.3 g). Chromatographic purification of the crude product was not possible. The crude product was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:8](/[C:10](=[CH:16]\OCC)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]>C1(C)C=CC=CC=1>[C:8]([C:10](=[CH:16][NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: CCO/C=C(\C#N)C(=O)OCC
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of pyridin-3-amine (C-1) (10.0 g, 106.3 mmol, 1.0 eq) and (E)-ethyl 2-cyano-3-ethoxyacrylate (C-2) (21.5 g, 127 mmol, 1.2 eq) in toluene (40 mL) is stirred at reflux under argon for 5 h and then allowed to cool to RT. The precipitate is collected by filtration, rinsed with a mixture of petroether and ethyl acetate (v/v=2:1, 3×10 mL), and then dried in vacuo to afford the product, ethyl 2-cyano-3-(pyridin-3-ylamino)acrylate (C-3).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[CH:23][N:22]=[C:21]([NH2:27])[C:20]=2[N:19]=[C:18]1[CH2:28][O:29][CH2:30][CH3:31]>>[NH2:27][C:21]1[C:20]2[N:19]=[C:18]([CH2:28][O:29][CH2:30][CH3:31])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:25]=2[C:24]([CH3:26])=[CH:23][N:22]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNC(=O)N(C)c1ccccc1

Procedure:
Using the method of Examples 147-164, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 411.2532.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35]([CH:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CN1CCC(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (26.2 mg, 67.5%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 92.5 mmol) and 1-methylpiperidine-4-carboxylic acid.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl>CN(C)C=O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]([F:13])([F:23])[F:24])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: Cc1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
Orcinol monohydrate (4.30 g, 30 mmol) in N,N-dimethylformarnide (20 mL) was added to a suspension of sodium hydride (1.5 g, 60 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at ambient temperature for 30 minutes. To the above solution was slowly added 2-trifluoromethylbenzyl chloride (5.0 g,25 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at ambient temperature for 3 hours. After carefully quenching with water (100 mL), the mixture was extracted with ethyl acetate (3×100 mL). The ethyl acetate solution was washed with brine (2×100 mL) and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (3:1 hexane/ethyl acetate) to give the title compound as a white solid (2.9 g, 41%). 1H-NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.8 Hz, 1 H), 7.68 (d, J=7.9Hz, 1 H), 7.56 (t, J=7.7 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 6.39 (s, 1 H), 6.28 (s, 2 H), 5.22 (s, 2 H), 4.79 (s, 1 H), 2.27 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].O>C1COCC1>[C:18]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=2[N:6]=1)(=[O:20])[CH3:19]
Reactant: Cc1ccc2ncsc2c1
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccc(C)cc2s1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of 6-methylbenzothiazole (6.1 g, 41 mmol) in anhydrous THF (150 ml) was cooled to -78° C. To the cooled solution was added, with stirring, n-butyl lithium (28.1 ml of 1.6 M n-BuLi-containing hexane solution, 45 mmol) dropwise under nitrogen atmosphere. Further, a solution of N,N-dimethyl acetamide (3.9 g, 45 mmol) in anhydrous THF (70 ml) was added dropwise to the mixture at the same temperature. After completion of the addition, the mixture was stirred for an hour, and then warmed to room temperature. The reaction mixture was poured into water, and then extracted with benzene. The extract was washed with water, dried over magnesium sulfate, and then evaporated. The resulting residual powders were subjected to purification using column chromatography on silica gel (eluant, n-hexane/ethyl acetate=95/5) to afford 2-acetyl-6-methylbenzothiazole (3.7 g, 47%) as a pale yellow powder, together with the starting material (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[CH:7]=[C:8]([NH:26][CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([CH3:24])[CH:15]=3)[C:10]=2[CH:25]=1.CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[CH:7]=[C:8]([NH:26][CH2:27][CH2:28][C:29]([F:31])([F:32])[F:30])[C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[C:10]=2[CH:25]=1
Reactant: COC(=O)c1ccc(-n2cnc3c(NCCC(F)(F)F)cc(Oc4cccc(F)c4)cc32)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-n2cnc3c(NCCC(F)(F)F)cc(Oc4cccc(F)c4)cc32)ccc1C(=O)O
Temperature: 23 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of 275 mg (564 μmol) methyl 4-{6-(3-fluorophenoxy)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzoate which was prepared according to intermediate example 10b in 12 mL tetrahydrofurane and 4 mL methanol were added 2.8 mL of a 1M aqueous lithium hydroxide solution and the mixture was stirred at 23° C. overnight. Water was added, the mixture was acidified by the addition of a 1M hydrochloric acid and extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 246 mg (88%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]3[C:28]([NH:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[O:29])(=[O:21])=[O:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:3]([O:2][C:1]([N:25]1[CH2:26][CH2:27][N:22]([S:19]([C:17]2[S:18][C:14]([C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:20])[C@@H:23]([C:28]([NH:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[O:29])[CH2:24]1)=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NOC2CCCCO2)C1
Yield: 82.1 %

Procedure:
A solution of ethyl chlorocarbonate (42 mg) in CHCl3 (1 ml) was added dropwise to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) and triethylamine (39 mg) in CHCl3 (2 ml) with cooling on an ice bath. The reaction mixture was stirred at said temperature for 30 minutes and the reaction was quenched by adding 3-(N,N-dimethylamino)propylamine (0.5 ml). The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 5% aqueous citric acid. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography eluted with AcOEt in hexane gradually from 40% to 60%, to give 142 mg of (2R)-4-ethoxycarbonyl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][OH:19])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[CH3:30]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][O:19][CH3:30])[C@@H:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (400 mg, 0.982 mmol) and Proton Sponge® (841 mg, 3.93 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. (icewater bath) was added trimethyloxonium tetrafluoroborate (290 mg, 1.963 mmol; weighed under N2), and the resulting mixture was stirred at 0° C. for 3 h, quenched with 1N HCl (20 mL), and extracted with CH2Cl2 (3×20 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to provide an oily white solid, which was purified by column chromatography on SiO2 (5→20% acetone/hexanes) to provide the title compound as a white, crystalline solid (321 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J=8.0 Hz, 2H), 6.94 (dd, J=7.7, 3.3 Hz, 3H), 5.10 (d, J=8.1 Hz, 1H), 5.08-4.98 (m, 1H), 4.20 (q, J=7.9, 6.9 Hz, 2H), 3.36 (t, J=6.5 Hz, 2H), 3.25 (s, 3H), 2.27 (dt, J=13.3, 6.8 Hz, 1H), 1.88 (ddt, J=10.8, 6.9, 3.9 Hz, 2H), 1.83-1.71 (m, 1H), 1.70-1.61 (m, 1H), 1.60-1.52 (m, 1H), 1.44 (s, 10H), 1.28 (d, J=6.5 Hz, 3H), 1.25-1.16 (m, 1H), 1.16-1.05 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 173.28, 159.46, 154.90, 129.61, 121.05, 115.38, 81.12, 79.86, 74.71, 70.79, 58.42, 52.99, 40.09, 34.12, 30.53, 28.33, 28.15, 19.07, 18.36; ESIMS m/z 422.3 ([M+H]+), 444.3 ([M+Na]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[C@@H:10]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([O:35][C:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37])[CH3:34].C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:41]3[CH:42]=[CH:43][C:38]([C:36]([O:35][CH2:33][CH3:34])=[O:37])=[CH:39][CH:40]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(Br)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3OCc3ccc4ccccc4c3)c2)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of (3R*,4R*)-4-(3-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (173.8 mg, 0.35 mmol), 4-ethoxycarbonylphenyl boronic acid (135.8 mg, 0.70 mmol), dimethoxyethane (4.5 mL), H2O (1.5 mL), tetrakis-(triphenylphosphin)-palladium (46.2 mg, 0.04 mmol) and Na2CO3 (111.3 mg, 1.05 mmol) is heated at reflux under argon for 14 h. The mixture is cooled to RT, dimethoxyethane is removed in vacuo and the residue is diluted with aqueous 2N Na2CO3 solution containing a few mL of concentrated NH4OH. The aqueous layer is extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the dark residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-(4′-ethoxycarbonyl-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a yellowish resin. A stirred mixture of this ester and CH3NH2 (8M in EtOH, 5 mL, 40 mmol) is heated at 80° C. for 24 h in a pressure bottle. The reaction mixture is evaporated in vacuo to afford (3R*,4R*)-4-(4′-methylcarbamoyl-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a viscous yellowish oil. A mixture of this compound (62.4 mg, 0.11 mmol) and HCl (5M in 2-propanol, 3 mL, 15 mmol) is stirred for 1 h at RT. The reaction mixture is evaporated in vacuo to afford 3′-[(3R*,4R*)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-biphenyl-4-carboxylic acid methylamide hydrochloride as a white solid. MS 451.7 [M+H]+; Rf 0.13 (DCM/MeOH 9:1).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27](O)=[O:28])[C:10]=2[C:30](O)=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)[CH3:34].O>C(O)(=O)C>[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[C:27](=[O:28])[C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]4=[C:9]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:10]=3[C:30]2=[O:31])=[CH:42][CH:43]=1)[CH3:34]
Reactant: O=C(O)c1c(C(=O)O)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 1,4-bis[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (2.0 g, 4.67 mmol) and ethyl(4-aminophenyl)acetate (1.67 g, 9.35 mmol) were heated to 120° C. in acetic acid (30 ml) for 2 hours. The mixture solidified on standing at room temperature overnight. Water was added and the solid collected by filtration and washed with water. This was dried under vacuum to give the title compound (2.65 g, 4.64 mmol). LC/MS: Rt=4.24, [MH]+ 572.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.N1C=CC=CC=1>O.C([O-])(O)=O.[Na+]>[CH3:2][N:3]([CH3:4])[C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1Br
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c2ncccc2c1N(C)C
Yield: 18 %

Procedure:
A solution of 18 g (0.22 mole) of dimethylamine hydrochloride in 50 ml of warm water was added to a stirred mixture of 30 g (0.11 mole) of 5-bromo-6-methoxy-8-nitroquinoline--Example 13A--30 g of NaHCO3 and 180 ml of pyridine. The mixture was heated under reflux for 30 hr, allowed to cool and filtered. The filtered solid was washed with acetone and the combined filtrate and washings were slowly diluted with water to 4 l. Unreacted 5-bromo compound separated first followed by product. Crystallization from methanol gave 4.9 g of 5-dimethylamino-6-methoxy-8-nitroquinoline (20% yield) as orange crystals which melted 79°-80°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.[O-]CCCC.[Na+].[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH2:30]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:11]1[C:10](=[O:20])[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:28]=1[F:27])=[N:7]2
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Reactant: Nc1ccc(F)cc1F
Agent: [Fe+2]
Agent: CCCC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1ccn2nc(Nc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (100 mg, 0.34 mmol) dissolved in toluene (1.5 mL) was added Pd(DBA) (3.1 mg, 0.0034 mmol), dppf (3.7 mg, 0.0068 mmol), sodium butoxide (23 mg, 0.238 mmol), and 2,4 difluoro aniline (43 mg, 0.34 mmol). The reaction was heated to 80° C. for 3 hours until complete by LCMS analysis. The reaction was passed through celite, condensed to an oil and purified via silica gel chromatography (EtOAc/CH2Cl2, MeOH) to yield the title compound.