Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]2=[CH:47]OC.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:65])[C:55]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)=[CH:56][CH:57]=1>>[F:64][C:61]1[CH:62]=[CH:63][C:58]([C:55]2[CH:56]=[CH:57][C:52]([CH2:51][NH:50][CH:47]=[C:38]3[C:37]4[C:42](=[CH:43][CH:44]=[C:35]([C:31]5[O:30][CH:34]=[CH:33][CH:32]=5)[CH:36]=4)[C:41](=[O:45])[NH:40][C:39]3=[O:46])=[CH:53][C:54]=2[OH:65])=[CH:59][CH:60]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Reactant: NCc1ccc(-c2ccc(F)cc2)c(O)c1
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNCc1ccc(-c2ccc(F)cc2)c(O)c1
Yield: 62 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-Furan-2-yl-4-methoxymethylene-4H-isoquinoline-1,3-dione (40 mg, 0.15 mmol) and 4-Aminomethyl-4′-fluoro-biphenyl-2-ol (33 mg, 0.15 mmol) in 62% yield: MS (ESI): 453.2 (M−1)−1.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:3]([CH3:4])=[CH:2]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:4][CH:3]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][CH2:2]1
Reactant: Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1CNc2ccccc21
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Skatole (26.5 g, 202 mmol) was dissolved in acetic acid (500 mL) and cooled to 15° C. Sodium cyanoborohydride (40 g, 637 mmol) was added in portions to this cooled solution. After the addition was complete, stirring was continued for 1 h at RT. Subsequently, water (100 mL) was added and after 15 min at RT, the mixture was evaporated under reduced pressure at 60° C. To the residue was added 0.5 L 5% aq. NaHCO3 and 0.5 L TBME and the organic layer was washed with 5% aq. NaHCO3 (2×250 mL), water (0.5 L), 1M aq. NaOH (100 mL), 5% aq. NaHCO3 (250 mL), and brine (250 mL). After drying over Na2SO4 and filtration, the solvent was removed by evaporation under reduced pressure. Yield: 23.3 g (87%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].N12CCN(CC1)CC2.Cl>C(OCC)(=O)C.O>[CH3:14][O:13][C:9](=[O:12])[C:10](=[CH2:11])[CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C(=O)OC)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 119 h

Procedure:
A mixture of benzaldehyde (63.67 g; 600 mmol), methyl acrylate (60 ml; 667 mmol) and 1,4-diazabicyclo [2.2.2] octane (13.46 g; 120 mmol) is stirred at ambient temperature for 119 hours. To the reaction solution is added water (60 ml), 37% hydrochloric acid (60 ml) and ethyl acetate (120 ml), and then, the organic phase is extracted. The resulting organic phase is washed twice with saturated saline (60 ml), dried over anhydrous sodium sulfate and filtered, then concentrated under reduced pressure, to give a crude product of the title compound at a yield of 108.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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.Cl[Pd]Cl.[Fe+2]>[NH2:39][C:40]1[N:41]=[CH:42][C:43]([C:27]2[CH:28]=[CH:29][C:24]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:16](=[O:17])[C:15]4[N:14]=[CH:13][N:12]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:11]=4[N:10]=3)=[CH:25][CH:26]=2)=[CH:44][CH:45]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Temperature: 100 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-9-phenyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,9-dihydro-purin-6-one (180 mg, 0.34 mmol) and 2-amino-5-bromopyridine (89 mg, 0.51 mmol) in anhydrous DMF (3 mL) was treated sequentially with Cs2CO3 (224 mg, 0.69 mmol) and Pd(dppf)2Cl2 (14 mg, 0.017 mmol). The reaction mixture was degassed with N2 and heated at 100° C. for 24 h. The reaction was cooled to room temperature, diluted with H2O, and extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated. The crude material was purified by flash column chromatography (silica, 30% EtOAc/CH2Cl2) to provide the title compound 2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one as a white solid. 1H NMR (CDCl3) δ (ppm) 8.19 (s, 1H), 7.95 (m, 2H), 7.72 (d, 2H), 7.61 (apparent t, 2H), 7.52 (apparent t, 1H), 7.42 (d, 2H), 7.35 (m, 4H), 7.17 (d, 2H), 6.95 (d, 1H); HPLC-MS calculated for C28H19ClN6O (M+H+): 491.1. Found: 491.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9]([O-])([O-])(OCC)[CH3:10]>>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:9][CH3:10])=[CH:7][N:6]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: Nc1ccc(Cl)nc1
Product: CCNc1ccc(Cl)nc1
Temperature: 67 °C
Reaction time: 27 h

Procedure:
A mixture of 10 g (0.078 mole) of 5-amino-2-chloropyridine and 50 ml of ethyl orthoacetate was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 60 ml of dry THF. Then, the solution was added dropwise to a suspension of 7.0 g of lithium borohydride in 100 ml of dry THF over a period of 15 minutes with constant stirring. After completion of dropwise addition, the mixture was refluxed with stirring for 27 hours. After cooling, the solvent was distilled off. To the residue were added 100 ml of ice-water and 35 ml of concentrated hydrochloric acid and the mixture was heated at 67° C. for a while. After cooling, the reaction mixture was adjusted to pH 7 with NaHCO3 and extracted with AcOEt (50 ml×3). The AcOEt layers were combined, washed with aqueous sodium chloride solution and dried over MgSO4. The AcOEt was distilled off and the residual crystals were collected by filtration, washed with hexane and dried. The procedure gave 9.2 g of the title compound as pale yellowish green crystals.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1.[CH3:19][CH2:18][CH:17]([C:2]([NH2:3])=[O:1])[CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCN=C=O
Agent: O=c1[nH]c2ncccc2o1
Solvent: C1COCCO1
Product: CCCC(CC)C(N)=O

Procedure:
100 mg (0.74 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 1 with 102.8 mg (0.809 mmol) of 1-isocyanatohexane in dioxane at 80° C. Yield: 77 mg (40%), M+H+: 264.12.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)CCO.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: OCCNCCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 80.3 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of diethanolamine and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 16.9 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1CCCCC1.[CH3:15][S:16]SC.Cl>[Zr].O.C(O)CC>[CH3:15][S:16][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8]
Reactant: Oc1ccc(Cl)cc1
Reactant: CSSC
Agent: [Zr]
Agent: Cl
Solvent: O
Solvent: CCCO
Solvent: C1CCCCC1
Product: CSc1cc(Cl)ccc1O
Temperature: 180 °C
Yield: 61.8 %

Procedure:
A mixture of 4-chlorophenol (15.0 g, 0.12 moles) and cyclohexane (8 ml) was distilled to remove cyclohexane and water. To the dry p-chlorophenol was added 3.3 g of zirconium n-propoxide in n-propanol consisting of 21.6% zirconium (0.008 mole) and 10.8% free propanol. The mixture was distilled at atmospheric pressure under nitrogen removing 1.0 g of n-propanol. To the resultant mixture was added methyl disulfide (7.1 g, 0.075 moles). The mixture was heated under nitrogen at reflux for 43 hours during which the temperature increased to 180° C. The mixture was cooled, hydrolyzed by addition of water, treated with concentrated HCl to dissolve solids, and extracted with ether. The ether extracts were dried over magnesium sulfate, filtered, and concentrated on a rotary flash evaporator. GC analysis of the concentrate indicated only two major components, 5.9 g of 4-chlorophenol and 8.1 g of 2-methylthio-4-chlorophenol (62% yield).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:27]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28]1>ClCCl>[CH:27]1([CH2:31][NH:32][C:24]([C:21]2[CH:20]=[CH:19][C:18]3[S:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH:8]([CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)[CH3:9])[C:23]=3[CH:22]=2)=[O:25])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reactant: NCC1CCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CCC3)cc21
Yield: 46.4 %

Procedure:
Using a procedure similar to that described in Example 15, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (3.4 g) in dichloromethane (100 cc) and cyclobutylmethylamine (4.5 g), and after recrystallization in isopropyl ether, N-cyclobutylmethyl-10-[(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.7 g) is obtained in the form of white crystals, m.p. 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:12])[CH2:10][NH2:11])=[CH:7][C:6]([CH2:13][CH3:14])=[C:5]([CH3:15])[N:4]=1.C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:12])[CH2:10][N:11]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:7][C:6]([CH2:13][CH3:14])=[C:5]([CH3:15])[N:4]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCc1cc(C(O)CN)c(OC)nc1C
Solvent: CCO
Product: CCc1cc(C(O)CN2C(=O)c3ccccc3C2=O)c(OC)nc1C
Reaction time: 6 h
Yield: 14.9 %

Procedure:
To a suspension of 2-methoxy-3-(2-amino-1-(R/S)hydroxyethyl)-5-ethyl-6-methylpyridine (345 mg, 1.64 mmol) in ethanol (5 mL) was added N-(carbethoxy)-phthalimide (373 mg, 1.70 mmol). The reaction was stirred for six hours as suspension dissolved. The solvent was evaporated and the viscous residue triturated with ethyl acetate/diethyl ether as product crystallized. By filtration 273 mg (49%) of pure product was collected, m.p. 134°-135° C. These mother liquors were flash chromatographed on silica gel and eluted with 20% ethyl acetate/80% hexane to give an additional 83 mg (15%) of product.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:27][NH2:28]>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:28][CH3:27])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Reactant: CN
Solvent: CN1CCCC1=O
Product: CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (25 mg, 63.71 μmol) and methylamine (2N in MeOH, 200 μl) in 300 μl of NMP is heated at 150° C. by microwave for 3 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 6.7 mg of 4-methylaminobenzene-sulfonic 2-(cyclopropanecarbonylamino)benzothiazol-6-yl ester (beige-colored solid).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:34])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(Oc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(Oc2ccccc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-phenoxypiperidin-1-yl)quinolin-7-yl]ethanone (0.0236 g, 0.0620 mmol) and ammonium acetate (0.0478 g, 0.620 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.15 mL, 0.15 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H25ClN3O (M+H)+: m/z=382.2; Found: 382.2.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.[NH4+].[Cl-]>C1COCC1.O>[CH3:16][C@H:8]([C@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)OC(=O)C[C@@H](O)C(=O)OC(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)OC(=O)[C@@H](O)[C@@H](C)C(=O)OC(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a cold (−78° C.) solution of diisopropyl-(R)-(+)-malate (9.4 mL; 45.8 mmol; 1.0 eq.) in anhydrous THF (17 mL) was added slowly a solution (1 M) of lithium bis(trimethylsilyl)amide (96.2 mL; 1.00 M; 96.2 mmol; 2.1 eq.) in THF. The temperature was raised to 20° C. over 30 minutes, than lowered again to −78° C. Iodomethane (3.4 mL; 55.0 mmol; 1.2 eq.) was added and the mixture stirred at RT for 16 hours. The reaction to mixture was then cooled to 0° C. and a saturated solution of NH4Cl was added. The resulting mixture was diluted with water, extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated under reduced pressure. The residue was then purified by chromatography (SiO2, 20/80 EtOAc/c-hex) to give the product (mixture of diastereoisomers) as a colourless oil (9.80 g, 92%).
Reaction SMILES: [C:1]1(=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16].[K+].[Br-]>O>[N+:15]([C:6]1[CH:7]=[CH:8][C:3]2[CH2:2][C:1](=[O:9])[C:4]=2[CH:5]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C1Cc2ccc([N+](=O)[O-])cc21
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Benzocyclobutenone (3.0 g, 25.42 mmol) was added slowly to concentrated sulfuric acid (6 mL) at -5° C.-0° C. with vigorous stirring. The resulting solution was further cooled to -10° C. and the mixture of concentrated sulfuric acid (3 mL) and nitric acid (70%, d 1.42, 2.0 mL) was added at such a rate that the solution temperature remained between -10° C. and -5° C. After the completion of addition of nitrating solution, stirring continued for 10 min. The reaction mixture was then poured into an ice slurry (30 g of ice in 30 mL of water). The product which precipitated out as yellow solids from water was collected by suction filtration and washed with water twice, aqueous sodium carbonate solution (10%) twice, and water twice consecutively. The solid product was recrystallized from methanol to give white fine crystals: 3.44 g (83.1%); mp 126°-127° C.; IR (KBr) 1342, 1522, 1785 cm-1 ; 1H NMR (200 MHz, CDCl3) 4.16 (s, 2H), 7.95 (d, 1H), 8.22 (s, 1H), 8.51 (d, 1H); MS (EI, m/e, relative intensity %) 163 (M+., 99.3), 135 (M+. -CO, 39.3), 89 (135 -.NO2, 100).
Reaction SMILES: [OH-].[Na+].CC(O)C.[F:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[CH:22]=[C:21]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C>[F:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[CH:22]=[C:21]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(Sc2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Sc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
10% Sodium hydroxide aqueous solution 1.0 mL was added to a suspension of 2-propanol 2.0 mL of methyl 2-(4-fluoroanilino)-4-(phenylthio)benzoate 0.21 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give 2-(4-fluoroanilino)-4-(phenylthio)benzoic acid 0.16 g of pale yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:18]2[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:20]([CH3:32])[CH:19]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClCC(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]1[O:49][C@H:48]1[CH2:50][OH:51]>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:18]2[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])=[C:20]([CH3:32])[CH:19]=2)([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:47][CH:48]([OH:49])[CH2:50][OH:51])=[C:12]([CH3:17])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OC[C@H]1CO1
Reactant: CC(=O)N1CCC(c2ccc(O)c(C)c2)(c2ccc(OCC(=O)C(C)(C)C)c(C)c2)CC1
Agent: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)N1CCC(c2ccc(OCC(=O)C(C)(C)C)c(C)c2)(c2ccc(OCC(O)CO)c(C)c2)CC1

Procedure:
In a manner similar to that described for Example 6B, 1-{4-[1-acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy)-3,3-dimethylbutan-2-one was prepared by using 1 equiv of 1-chloropinacolone and cesium carbonate. 1-{4-[1-Acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy}-3,3-dimethylbutan-2-one was then alkylated with (S)-glycidol as in Example 1H to yield 1-(4-(1-acetyl-4-[4-(2,3-dihydroxypropoxy)-3-methylphenyl]-piperidin-4-yl}-2-methylphenoxy)-3,3-dimethylbutan-2-one.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH:19]=[C:18]([F:28])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:28][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:30])([CH3:29])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCCC3=O)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
A mixture of 2-[3-fluoro-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.25 g, 0.61 mmol), lithium hydroxide hydrate (0.26 g, 6.1 mmol), water (2 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-fluoro-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (77 mg, 33%) as a white solid: LC/MS m/e calcd for C22H23FN2O3 (M+H)+: 383.4, observed: 383.2.
Reaction SMILES: C([NH:18][CH2:19][C@H:20]([C:22]([OH:24])=[O:23])[OH:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1.[CH:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1)=[O:32].C1C=CC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C>CN(C=O)C.CN1CCCC1=O.C(#N)C>[CH:31]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:18][CH2:19][C@@H:20]([OH:21])[C:22]([OH:24])=[O:23])=[O:39])=[CH:40][CH:41]=1)=[O:32]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(NC[C@@H](O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound (R)-Fmoc-isoserine was added 500 μL of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with N-methyl-2-pyrrolidinone (6×1 mL). Then, 200 μmol 4-formylbenzoic acid (30 mg) and 200 μmol HOBt (31 mg) was dissolved in N-methyl-2-pyrrolidinone (500 μL) and added to the resin followed by 200 μmol diisopropyl carbodiimide (25.2 mg) dissolved in acetonitrile (500 μL). The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with N-methyl-2-pyrrolidinone (3×1 mL).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[Si:10]([C:14]#[CH:15])([CH3:13])([CH3:12])[CH3:11]>C(OCC)C.[Cu]I.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>[F:1][C:2]1[CH:8]=[C:7]([C:15]#[C:14][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Fluoro-4-iodoaniline (5.00 g, 21.1 mmol), CuI (90 mg, 0.42 mmol), and (Ph3P)2PdCl2 (300 mg, 0.42 mmol) were weighed into a flask which was sealed and flushed with N2. A solution of TMS-acetylene (2.28 g, 23.2 mmol) in TEA (20 mL) was added, then the entire mixture stirred 15 hours at room temperature. The reaction mixture was diluted with diethyl ether (200 mL), filtered through Celite®, then all solvents removed under reduced pressure. The resulting dark brown oil was purified by filtration through a plug of flash silica (5% EtOAc/hexanes as eluant) to afford the desired product as a pale brown oil which rapidly solidified to give a crystalline solid (3.85 g, 88%); m.p. (EtOAc/hexanes) 45–47° C. 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=11.7, 1.8 Hz, 1 H), 7.06 (ddd, J=8.3, 1.8, 1.0 Hz, 1 H), 6.66 (dd, J=9.4, 8.3 Hz, 1 H), 3.86 (br s, 2 H), 0.22 (s, 9 H). Anal. Calcd for C11H14FNSi: C, 63.7; H, 6.8; N, 6.8. Found: C, 63.7; H, 6.9; N, 6.7.