Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([Br:21])=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(C)C>C(#N)C.[Pt]>[NH2:22][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[NH:10][CH2:9][CH2:8][NH:7][C:6](=[O:25])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Yield: 91.1 %

Procedure:
A solution of tert-butyl[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]carbamate (165.0 g, 401.2 mmol) in acetonitrile (3.3 L) and, isopropanol (990 mL) and 5% platinum on carbon (13.2 g) were added to a Parr vessel, which was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to provide 139.29 g of tert-butyl [2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]carbamate as a yellow solid. The product was suspended in a mixture of dichloromethane (4 mL/g) and chloroform (8 mL/g), and the suspension was divided into two equal portions.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:27])=[C:9]([S:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19])[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:28])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([S:18]([C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])=[C:8]2[CH3:27]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(S(=O)c3ccc(Cl)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1S(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzenesulfinyl)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.050 g), methanol (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.57 mL) was stirred at room temperature for 3 hours. The pH of the mixture was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a pale yellow solid, 0.029 g.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[CH:11][C:12]1[C:13]([O:22]CC2C=CC=CC=2)=[N:14][C:15]([CH3:21])=[C:16]([CH:18]([OH:20])[CH3:19])[CH:17]=1.C(OC1C=CC=CN=1)C1C=CC=CC=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:22])[NH:14][C:15]([CH3:21])=[C:16]([CH:18]([OH:20])[CH3:19])[CH:17]=1
Reactant: Cc1nc(OCc2ccccc2)c(C=Cc2nc3ccccc3o2)cc1C(C)O
Agent: c1ccc(COc2ccccn2)cc1
Product: Cc1[nH]c(=O)c(CCc2nc3ccccc3o2)cc1C(C)O

Procedure:
Following substantially the same procedure described in Example 3, Step F, but substituting 3-[2-(benzoxazol-2-yl)ethenyl]-5-(1-hydroxyethyl)-6-methyl-2-benzyloxypyridine for the benzyloxypyridine compound used therein, the title compound is obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:29][C:30]([N:32]([CH2:34][C:35](O)=[O:36])[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N>C(Cl)Cl.C(N(CC)CC)C>[CH2:22]([O:29][C:30](=[O:31])[N:32]([CH2:34][C:35](=[O:36])[NH:21][CH2:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:19][CH:18]=2)[CH:13]=[CH:14][CH:15]=1)[CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of C-(6-benzenesulfonyl-naphthalen-1-yl)-methylamine, (Benzyloxycarbonyl-methyl-amino)-acetic acid, 1-hydroxybenzotriazole, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide and triethylamine in methylene chloride is stirred at room temperature. The reaction is quenched by addition of water, and the mixture is eluted through silica gel to give {[(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-carbamoyl]-methyl}-methyl-carbamic acid benzyl ester.
Reaction SMILES: C1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8](CC)=[N:7]2)CCCC1.[CH3:17]N(C)CCOC1C=C(C=CC=1)C=O>>[N:6]1[C:10]2=[N:11][CH:17]=[N:14][C:12](=[O:13])[C:9]2=[CH:8][N:7]=1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CN(C)CCOc1cccc(C=O)c1
Product: O=C1N=CN=C2N=NC=C12
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.50 g, 15.74 mmol), 3-[2-(dimethylamino)ethoxy]benzaldehyde (3.95 g) and xylenes (10 ml) was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, the solvent was stripped, and the residue was partitioned between chloroform and water. The layers were separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford, as an oil, 1-cyclopentyl-3-ethyl-6-[3-[2-dimethylamino)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one labelled as [Example 23(b)]. The free base was treated with ethanolic HCl to afford the product as the hydrochloride salt [labelled as Example 23(c)].
Reaction SMILES: Cl[CH:2]1[O:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16].C(N(CC)CC)C.[O-:25][CH2:26][CH3:27].[Na+]>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:5]1[C:4](=[O:15])[C:3]([CH3:17])([CH3:16])[CH:2]([O:25][CH2:26][CH3:27])[O:6]1
Reactant: CC[O-]
Reactant: CC1(C)C(=O)N(Cc2ccccc2Cl)OC1Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC1ON(Cc2ccccc2Cl)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To a stirred solution of 3.0 grams (0.011 mole) of 5-chloro-2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (Example 23 (A)) in 30 ml of absolute ethanol was added dropwise 1.2 grams (0.012 mole) of triethylamine. Upon completion of addition the reaction mixture was heated under reflux for 18 hours; thin layer chromatography of the reaction mixture indicated no reaction had taken place. The reaction mixture was cooled, 0.74 gram (1 equiv.) of sodium ethoxide was added, and the reaction mixture was stirred at ambient temperature for two hours; again thin layer chromatography on the reaction mixture indicated that no reaction had taken place. The reaction mixture was filtered and diluted with 150 ml of methylene chloride. The mixture was washed with two 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled at 80°/3.3 Pa. using a short-path distilling system. Nuclear magnetic resonance spectroscopy indicated 83% of the distillate to be the desired product. The distillate was subjected to column chromatography on silica gel, using 20% ethyl acetate in heptane for elution. The appropriate fractions were combined and concentrated under reduced pressure to give 1.3 grams of 2-[(2-chlorophenyl)methyl]-5-ethoxy-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[Cl:12].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:12]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C(=O)O)cc1Cl
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
To a solution of methyl 4-amino-3-chlorobenzoate (3.3 g) in ethanol (53 ml) was added 8N aqueous sodium hydroxide solution (4.4 ml), and the mixture was stirred at 40° C. for 3.5 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in water. The obtained aqueous solution was washed with diethyl ether and neutralized with 1N aqueous hydrochloric acid solution. The precipitated insoluble material was collected by filtration and air-dried to give the title compound as a pale-brown powder (3.0 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=2)[CH:19]=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:23].[NH:24]1[CH2:28][CH2:27][C@@H:26]([C:29]([OH:31])=[O:30])[CH2:25]1.CC(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=2)[CH2:19][N:24]2[CH2:28][CH2:27][C@@H:26]([C:29]([OH:31])=[O:30])[CH2:25]2)[C:9]([F:11])([F:12])[F:10])=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc([C@H](Nc2ccc(C)c(C=O)c2)C(F)(F)F)ccc1Cl
Reactant: O=C(O)[C@@H]1CCNC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc([C@H](Nc2ccc(C)c(CN3CC[C@@H](C(=O)O)C3)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of aldehyde INT 33 (2.50 g, 7.32 mmol) and (R)-pyrrolidine-3-carboxylic acid (0.93 g, 8.05 mmol) in MeOH (74 mL) was added HOAc (0.42 mL, 7.32 mmol) followed by PS—CNBH3 (2.5 mmol/g, 2.93 g, 7.32 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through Celite. The filtrate was concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and water. The aqueous layers were extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH) to afford the title compound Example 21.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:15]=[O:16])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:15]=[O:16])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]2[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1[nH]c2cccc(Br)c2c1C=O
Reactant: BrCCCOc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C=O)c2c(Br)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of EXAMPLE 107A (1.76 g) in N,N-dimethylformamide (10 mL) was added 1-(3-bromopropoxy)naphthalene (1.66 g) and Cs2CO3 (6.10 g). The mixture was stirred for 3 days at room temperature. The mixture was diluted with ethyl acetate (300 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water (×3) and brine and dried over Na2SO4. After filtration, concentration of solvent gave crude product, which was purified by column chromatography (5% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])C=CC=CC=1>C(OC)(C)(C)C.CN(C=O)C.CCCCCCC>[CH2:38]([O:37][C:35](=[O:36])[C:34]([CH3:40])=[C:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:39]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (4-fluoro-phenyl)-acetic acid (22.33 g, 144.9 mmol) in 100 mL of methyl tert-butyl ether and 250 μL of DMF was added 13.02 mL (146.3 mmol) of oxalyl chloride at room temperature dropwise over 30 minutes. The resulting mixture was stirred at room temperature for an additional 20 minutes (HPLC indicated completed reaction), and then the entire solution was added dropwise over 1 hour to a solution of N,N-diisopropylethylamine (50.48 mL, 289.8 mmol) and ethyl 2-(triphenylphosphoranylidene)propionate (50.0 g, 138.0 mmol) in 100 mL of methyl tert-butyl ether, while maintaining the internal temperature between 0-15° C. After the addition was complete, the reaction mixture was stirred for an additional 10 minutes at 0-10° C., when HPLC indicated a completed reaction. The reaction mixture was then diluted with 100 mL of heptane, and stirred for 30 minutes at 0-10° C. The resulting solid was filtered and washed with 2×100 mL of 1:1 methyl tert-butyl ether:heptane. The filtrate and the washings were combined and washed with 100 mL of water, 100 mL of 1M citric acid, 2×100 mL of water, then concentrated azeotropically at 25° C./60 mmHg to a total volume of ˜40 mL. The residue was diluted with 60 mL of methyl tert-butyl ether. This solution was then directly used for the next step.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1>COCCOC.O.C(OCC)(=O)C.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.[Pd]>[N:25]1[N:26]=[CH:27][CH:28]([C:2]2[S:6][CH:5]=[C:4]([C:7]([N:9]3[CH:18]4[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][CH2:11][CH2:10]3)=[O:8])[CH:3]=2)[CH:29]=1
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: OB(O)c1cn[nH]c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1csc(C2C=NN=C2)c1)N1CCCC2CCCCC21
Temperature: 140 °C
Yield: 21.1 %

Procedure:
cis-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.15 mmol) was added to a solution of caesium carbonate (0.15 mmol), 4-pyrazoleboronic acid (0.3 mmol) and palladium tetrakis(triphenylphosphine) (0.03 mmol) in DME (6 mL), IMS (2 mL) and water (0.001 mL). The reaction mixture was heated by microwave irradiation to 140° C. for 20 minutes and then diluted with ethyl acetate (5 mL) and washed with water. The organic solution was dried and filtered and the solvent evaporated. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound as a pale yellow oil (10 mg). LCMS m/z 316.27 [M+H]+ RT=9.34 min. (Analytical Method 2).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[NH3:19]>CO>[NH2:1][C@H:2]([C:15]([NH2:19])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of Tyr(3-tBu)-OCH3 (1.5 g, 5.97 mmol) in MeOH (10 ml), aqueous ammonia (10 ml) was added and stirred at room temperature overnight. The mixture was evaporated to remove the solvent under reduced pressure and the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=10:1), giving Tyr(3-tBu)-NH2 (1.4 g, 99%).
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].C1(C)C=CC=CC=1.[O:19]1[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20]1>O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:19][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][O:11][C:8]1[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 388.6 %

Procedure:
The sodium salt of 4-nitrophenol (28.19 g, 0.175 mol) was dissolved in water (50 mL) and toluene (300 mL) and tetrabutylammonium sulfate (6.0 g) was added. 1,2-Epoxydecane (27.3 g, 0.175 mol) was added to this mixture and the reaction was heated at 100° C. for 5 days. The toluene layer was separated and washed with water (4×75 mL), 1N hydrochloric acid (2×75 mL) and water (75 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed. The crude product was purified by silica gel chromatography (2–3% methanol/methylene chloride) to afford 4-(2-hydroxy-1-decyloxy)nitrobenzene as a pale oil (20 g, 0.68 mol, 39% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: Fc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(F)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 49 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 8 mg (0.21 mmol) of 60% sodium hydride, 40 mg (0.21 mmol) 2-bromomethyl-6-fluoro-pyridine and 0.8 mL of N,N-dimethylformamide. Yield: 28 mg of a white solid: LC-MSD, m/z for C24H19FN2O2 [M+H]+=387.3; HPLC retention time: 2.6 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([CH2:25]OS(C)(=O)=O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([CH2:25][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][C:9]2=[O:13])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2c(c1)NC(=O)CC2
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Product: COc1ccc2c(c1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)CC2
Yield: 71 %

Procedure:
Using the procedure of Example 2, step 2.i, but starting from 3,4-dihydro-7-methoxy-2(1H)-quinolinone (prepared according to WO 2006/134378; 886 mg) and 3-[[(methylsulfonyl)oxy]methyl]-1-azetidinecarboxylic acid tert-butyl ester (1459 mg; prepared according to WO 02/066470), the title compound was isolated as a colourless oil (1223 mg; 71% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(OCc2ccccc2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [4-(benzyloxy)-2-chlorophenyl]acetate (1.0 g, 3.00 mmol) in DCM (8 ml) was treated with TFA (6.94 ml, 90 mmol) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 299 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(C(C)C)C(C)C.CCOC(C)=O>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(Nc2cnc3ccccc3c2)n1

Procedure:
A mixture of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), 3-aminoquinoline (1.1 g, 7.79 mmol) and DIEA (2.0 mL, 11.5 mmol) in IPA (8 mL) was heated to reflux for 48 h. The mixture was poured into EtOAc (200 mL) and washed with H2O (100 mL). The organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified via medium pressure liquid chromatography using 50:50 EtOAc/hexanes followed by 100% EtOAc followed by 5:95 MeOH/CH2Cl2 followed by 1.0:10:90 conc. NH4OH/MeOH/CH2Cl2 as the solvent system. (2-Chloropyrimidin-4-yl)-quinolin-3-yl-amine was obtained as a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[C:3]=1[O:17][CH3:18].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:14]([OH:16])[CH3:15])[C:3]=1[O:17][CH3:18]
Reactant: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(C(C)O)cc2c(c1Br)C(C)(C)CCC2
Temperature: 25 °C

Procedure:
To a solution of 1-(4-bromo-3-methoxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound A-93, 12.1 g, 39 mmol) in ethanol (250 mL) was added sodium borohydride (741 mg, 19.5 mmol). After heating to reflux for 2 h the mixture was cooled to room temperature, quenched with 10% HCl and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a colorless syrup. The material was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.O(C(C)C)C(C)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[S:30])[CH:23]=1>>[F:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([N:2]([CH3:1])[CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:8]2)=[S:30])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)N1CCC(NC)CC1
Reactant: Fc1cccc(N=C=S)c1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)N1CCC(N(C)C(=S)Nc2cccc(F)c2)CC1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred solution of 91 parts of ethyl 4-(methylamino)-1-piperidinecarboxylate in 420 parts of 2,2'-oxybispropane were added dropwise 75 parts of 1-fluoro-3-isothiocyanatobenzene. Upon completion, stirring was continued for 1 hour. The precipitated product was filtered off and dried, yielding 150 parts (90%) of ethyl 4-[[(3-fluorophenyl)aminothioxomethyl]methylamino]-1-piperidinecarboxylate; mp. 175.2° C. (17).