Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:49][CH:46]3[CH2:47][CH2:48][O:43][CH2:44][CH2:45]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NC4CCOCC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and tetrahydro-2H-pyran-4-amine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH3:10])[CH:4]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH2:10][C:18](=[O:20])[CH3:19])[CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: COc1cc(C)nc(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)nc(CC(C)=O)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-methoxy-2,6-dimethylpyridine (1.56 g) in tetrahydrofuran (15 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 9.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.59 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=2:1) to give 1-(4-methoxy-6-methylpyridin-2-yl)propan-2-one (1.75 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:11])[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2Cl)c1

Procedure:
5-Bromo-2-chlorobenzoic acid (132 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5](=[O:24])[CH2:6][C:7]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(O)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+]>O1CCCC1>[CH:18]1([C:7]2([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[O:25][C:3](=[O:2])[CH:4]=[C:5]([OH:24])[CH2:6]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)CC(=O)CC(O)(CCc1ccc(O)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude 5-cyclohexyl-5-hydroxy-7-(4-hydroxy-phenyl)-3-oxo-heptanoic acid methyl ester (prepared in the previous paragraph) was dissolved in tetrahydrofuran (100 mL) and treated with 0.2N NaOH (900 mL) as described in General Method 7. The reaction was stirred for 3 hours at room temperature and then worked up as usual. The organic extracts obtained were combined, dried (MgSO4) and concentrated. Purification was accomplished by flash chromatography using CH2Cl2 :MeOH (99:1 to 98:2) to give the desired product as a solid, m.p. 52°-58° C. 1H NMR (CDCl3) δ 1.0-1.9 (m, 12 H), 1.9-2.1 (m, 1 H), 2.5-2.7 (m, 3 H), 2.8 (d, 1 H), 3.4 (s, 2 H), 6.75 (d, 2 H), 7.05 (d, 2 H).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH2:6][CH2:7][F:8])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:6][CH2:7][F:8])[CH3:9])#[N:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CCF
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)(CCF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-4-fluoro-2-methylbutanonitrile hydrochloride product from Example 72A was initially charged in 165 ml of tetrahydrofuran/water (1:1), and 28.57 g (206.71 mmol) of potassium carbonate and 9.46 g (55.46 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.72 g (10.1 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 5.04 g of the target compound were obtained (38% of theory over two stages, 96% purity).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH:12]=[CH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9].CC([O-])=O.[Na+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1(/[C:13](/[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:20])=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=CCC(=O)OCC
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C(/CC(=O)OCC)c1ccccc1
Temperature: 130 °C
Yield: 28 %

Procedure:
A solution of iodobenzene (1.08 ml, 9.67 mmol) in DMA (5 ml) was added dropwise to a solution of diethylglutaconate (2 g, 10.74 mmol), Pd(OAc)2 (250 mg, 1.07 mmol), NaOAc (880 mg, 10.74 mmol) in DMA (5 ml) at 115° C. under argon. After heating for 8 hours at 130° C., the reaction was cooled, diluted with CH2CI2 (60 ml), and washed with water (4×10 ml). The organic layer was washed with sat. aq. NaHCO3 (20 ml), brine (20 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The dark oil was purified by column chromatography using CH2Cl2 as the eluent. The product oil was dried overnight in vacuo giving diethyl (2Z)-3-phenylpent-2-ene-1,5-dioate in 28% yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[BrH:28]>>[Br:28][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2
Reactant: COc1cc2nc(N3CCc4c(CO)cccc4C3)[nH]c(=O)c2cc1OC
Reactant: Br
Product: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
2-(5-Hydroxymethyl-3,4-dihyd ro-1H-isoquinolin-2-yl)-6,7-dimethoxy-1H-quinazolin-4-one 22a (0.2 g, 0.54 mmol) was dissolved to room temperature in 5 mL of 48% hydrobromic acid and stirred to room temperature for 24 h. The precipitated product was separated by filtration, rinsed with water, dried to yield 0.21 g (91%) 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH:22][CH2:21][CH:20]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:19]2>C1COCC1>[CH2:25]([N:24]([CH2:28][CH2:29][CH3:30])[CH:20]1[CH2:19][C:18]2[C:23]3=[C:14]([O:13][C:1](=[O:2])[N:22]3[CH2:21]1)[CH:15]=[CH:16][CH:17]=2)[CH2:26][CH3:27]
Reactant: CCCN(CCC)C1CNc2c(O)cccc2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cccc3oc(=O)n(c23)C1
Reaction time: 0.08 h
Yield: 86.6 %

Procedure:
Carbonyldiimidazole (0.46 g, 2.8 retool) was added to a stirred solution of 1,2,3,4-tetrahydro-8-hydroxy-N, N-dipropyl-3-quinolinamine (0.59 g, 2.4 mmol) in THF (10 mL). After 5 minutes, the solvent was removed and the residue was dissolved in ethyl acetate and chromatographed on silica gel using 5% ethyl acetate in hexane as the initial eluant to give 0.57 g of 5-(dipropylamino)-5,6-dihydro-2H,4H-oxazolo(5,4,3-ij)quinolin-2-one as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:13]1([CH2:12][CH2:11][CH2:10][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCc1ccccc1
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCC1CCCN(CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 10.07 g (87.43 mM) of 3-piperidinemethanol and 19.1 g (96.2 mM) of 1-bromo-3-phenylpropane in 150 ml of acetonitrile was added 18.1 g (131 mM) of potassium carbonate and the mixture was stirred at room temperature for one day. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to provide crude 1-(3-phenylpropan-1-yl)piperidine-3-methanol. This crude product was not purified but used as it was in the next reaction. To a solution of this crude 1-(3-phenylpropan-1-yl)piperidine-3-methanol and 14.6 ml (105 mM) of triethylamine in 150 ml of tetrahydrofuran was added a solution of 11.0 g (96.2 mM) of methanesulfonyl chloride in 50 ml of tetrahydrofuran dropwise under ice-cooling and the mixture was further stirred at the prevailing temperature for 0.5 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was dissolved in 500 ml of N,N-dimethylformamide, followed by addition of 17.8 g (96.2 mM) of potassium phthalimide, and the mixture was stirred at 100° C. overnight. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br-].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: Clc1ccc(/C=C/CCCBr)cc1

Procedure:
4-Chlorobenzaldehyde (1.0 g) and 4-bromobutyl-triphenylphosphonium bromide (4.08 g) were treated in the same manner as in Preparation Example 83 to obtain the title compound.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[O:11][C:12]=1[CH3:13])(=O)=O.O[C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH:25]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:26][O:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(OCC)C>[C:23]([CH:26]1[CH:25]([C:30]([OH:32])=[O:31])[CH2:24][C:23]2[C:28](=[CH:29][C:20]([O:5][CH2:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[S:15][CH:16]=[CH:17][CH:18]=4)[O:11][C:12]=3[CH3:13])=[CH:21][CH:22]=2)[O:27]1)([CH3:28])([CH3:24])[CH3:22]
Reactant: Cc1oc(-c2cccs2)nc1CCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc2c(c1)OC(C(C)(C)C)C(C(=O)O)C2
Temperature: 25 °C

Procedure:
2-(5-methyl-2-thien-2-yl-1,3-oxazol-4-yl)ethyl methanesulfonate (947 mg, 3.3 mmol), tert-butyl 7-hydroxychromane-3-carboxylate (750 mg, 3 mmol) and potassium carbonate (1.24 g, 9 mmol) were mixed in CH3CN and refluxed under N2 atmosphere overnight. After the completion of the reaction (TLC), the reaction mixture was cooled to room temperature and diluted with 30 ml of diethyl ether and passed through a small pad of silica. Silica was washed with 100 ml of ether and the ether solution was evaporated to give the product which was purified by column chromatography on silica using ethyl acetate and hexanes as eluent (699 mg, 53%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[N:6]=[CH:7][C:2]([CH:17]=[O:16])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc(Oc2ccc(Br)cn2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a mixture of 5-bromo-2-(4-fluoro-phenoxy)-pyridine (940 mg, 3.5 mmol) described in Manufacturing Example 75-1-1 and tetrahydrofuran (10 mL) was added n-butyl lithium (1.7 mL, 1.5 M n-hexane solution, 2.6 mmol) under nitrogen atmosphere at −78° C., which was stirred for 30 minutes at that temperature. N,N-dimethylformamide (0.54 mL, 7.0 mmol) was added to the reaction mixture at the same temperature, and the temperature was gradually raised to 0° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (280 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CO[CH:16](OC)[CH2:17][CH:18](OC)OC.O.[NH4+].[OH-]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]3[N:13]=[CH:16][CH:17]=[CH:18][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(CC(OC)OC)OC
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2cc3ncccn3n2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazole-5-amine (5.0 g, 0.028 mol) in acetic acid (50 mL) is added 1,1,3,3-tetramethoxypropane (5.79 g, 0.035 mol). The mixture is stirred at 110° C. for 1 h. The reaction mixture is then poured into water, basified with NH4OH and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. 6.8 g (79%) of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine are obtained as a beige solid which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH2:2][C:3]#[CH:4].O1CCCC1.[CH2:21]([C:28]1[S:29][CH:30]=[C:31](Br)[N:32]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH2:21]([C:28]1[S:29][CH:30]=[C:31]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[N:32]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: Brc1csc(Cc2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1csc(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To 143 mg of dichlorobis(triphenylphosphine)palladium, 38 mg of copper iodide, and 0.80 g of N-(3-butynyl)phthalimide were added 9 ml of tetrahydrofuran, 1.02 g of the 2-benzyl-4-bromothiazole obtained in the foregoing stage, and 2.3 ml of triethylamine in a nitrogen atmosphere, and the mixture was stirred under reflux for 4 hours. After the stirring, the reaction mixture was cooled to room temperature and the solids were filtered. After concentrating the filtrate, the residue was purified by column chromatography (Wakogel C-200; toluene:ethyl acetate=9:1) to give 1.00 g of a phthalimide compound.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:13]([O:15][CH2:16][CH2:17][O:18][C:19](ON1C(=O)CCC1=O)=[O:20])=[O:14]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:20])=[O:14])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(C(=O)OCCOC(=O)ON2C(=O)CCC2=O)cc1OC
Reactant: NC1(C(=O)O)CC1
Product: COc1ccc(C(=O)OCCOC(=O)NC2(C(=O)O)CC2)cc1OC
Yield: 72.9 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.122 g, 1.21 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3,4-dimethoxybenzoate (0.4 g, 1.01 mmol) were reacted to provide 0.260 g (68% yield) of the title compound (14) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 171.8-173.6° C. 1H NMR (CDCl3, 400 MHz): δ=7.69 (d, 1H), 7.47 (s, 1H), 7.13 (d, 1H), 6.83 (d, 1H), 5.52 (s, 0.3H), 5.43 (s, 0.7H), 3.98 (d, 6H), 1.62 (m, 5H), 1.31 (br s, 2H). MS (ESI) m/z 375.99 (M+Na)+; 352.02 (M−H)−.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[BrH:37].N([O-])=O.[Na+]>C(#N)C.O>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A stirred suspension of 6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.421 g, 0.773 mmol) in 25 mL of acetonitrile was treated with 25 mL of 48% aqueous HBr and the resulting suspension cooled in an ice water bath. To the mixture was added a solution of sodium nitrite (0.056 g, 0.812 mmol) in 2 mL of water. After stirring at 0° C. for 30 minutes an additional 14 mg portion of sodium nitrite in 1 mL of water was added. After stirring at 0° C. for another 30 minutes, the mixture was treated with CuBr (0.130 g, 0.906 mmol) in four portions over 5 minutes. The mixture was warmed to 60° C. for 30 minutes and then cooled to RT. The mixture was partitioned between EtOAc and 5% aqueous sodium bisulfite. The EtOAc solution was washed with 5% aqueous sodium bisulfite (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient from hexane to 3:7 hexane/EtOAc) followed by recrystallization from hexane/EtOAc to give the title compound (0.212 g, 45%) as a white solid. LCMS (m/z, ES+)=609 (M+H+).
Reaction SMILES: CS(C)=O.Br[CH:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][N:14]=2)[N:9]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:8](=[O:30])[C:7]1([CH3:32])[CH3:31].C(=O)([O-])[OH:34].[Na+]>O>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6](=[O:34])[C:7]([CH3:32])([CH3:31])[C:8](=[O:30])[N:9]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(Br)c3ncc(Cl)cc32)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(=O)c3ncc(Cl)cc32)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
To a dimethylsulfoxide solution (8 ml) of tert-butyl 4-(4-bromo-7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (375 mg) was added sodium hydrogen carbonate (871 mg), followed by stirring at 100° C. for 6 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The collected organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After the resulting residue was dissolved in dichloromethane (14 ml), manganese dioxide (684 mg) was added and stirred for 50 minutes, and further manganese dioxide (690 mg) was added and stirred for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-3,3-dimethyl-2,4-dioxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (270 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N[C:22]1C=CC=C(C)C=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 100 %

Procedure:
(RK1-1-27B) I This compound was prepared according to the procedure described for compound 11a except using m-toluidine to obtain required product as a light tan solid, (264 mg, 100%). Mp=121-124° C. (lit 138-139° C. Tetrahedron 62(25), 6100-6106; 2006); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.90 (br s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.56 (br s, 1H).