Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:29][N:28]([CH3:30])[C:26]([C:3]1[C:2]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1)=[O:27]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1-c1cnn(C)c1
Temperature: 125 °C

Procedure:
Phenylmethyl 5-bromo-4-[(dimethylamino)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 39; 195 mg) was redissolved in 1,2-dimethoxyethane (5 ml) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103 mg, 0.49 mmol), tripotassium phosphate (168 mg, 0.79 mmol) and Pd(Ph3P)4 (34.3 mg, 0.03 mmol) were added. The mixture was heated at 125° C. for 50 minutes. Ethyl acetate (10 ml) and water (10 ml) were added. The organic layer was separated and dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 1:1 ethyl acetate/cyclohexane-10% 2M NH3 in CH3OH/dichloromethane) gave the title compound as a brown gum. 195 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1>CN(C)C=O>[Br:9][C:10]1[CH:11]=[N:12][C:13]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:14][CH:15]=1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)c1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ncc(Br)cn1
Temperature: 50 °C
Yield: 48.4 %

Procedure:
A solution of N,N-dimethylethanolamine (0.23 ml, 2.3 mmol) in dry dimethylformamide (5 ml) was treated with sodium hydride (60% suspension in mineral oil, 0.092 g, 2.3 mmol) and heated at 50° C. for 30 minutes. The product from Step 2 (0.50 g, 2.1 mmol) was added and the reaction heated at 50° C. overnight. After cooling to room temperature the reaction mixture was applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and chromatographed on silica gel eluting with 0.880 ammonia/methanol/dichloromethane solution (0.1:1.9:98 and 0.5:4.5:95) to afford the title compound (0.25 g, 48%); 1H NMR (CDCl3) 8.52 (2H, s), 4.45 (2H, t, J 8 Hz), 2.74 (2H, t, J 8 Hz), 2.33 (6H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.Br.[NH:39]([C:41]1[NH:42][CH2:43][CH2:44][N:45]=1)[NH2:40].C1C=CC(CNC(CN2C3C(=CC=CC=3)C(C=O)=C2)=O)=CC=1>CN(C=O)C.FC(F)(F)C(O)=O>[NH:45]1[CH2:44][CH2:43][N:42]=[C:41]1[NH:39][N:40]=[CH:35][C:27]1[NH:28][C:29](=[O:34])[C:30]2[C:25]([CH:26]=1)=[CH:24][C:23]1[CH2:22][CH2:21][C:18]3([C:17](=[O:37])[C:4]4=[C:5]([OH:16])[C:6]5[C:7](=[O:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10](=[O:12])[C:11]=5[C:2]([OH:1])=[C:3]4[C:19]3=[O:20])[C:32]=1[C:31]=2[OH:33]
Reactant: NNC1=NCCN1
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Agent: Br
Agent: O=Cc1cn(CC(=O)NCc2ccccc2)c2ccccc12
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C1(CCc2cc4cc(C=NNC5=NCCN5)[nH]c(=O)c4c(O)c21)C3=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 2.05 mg (11.3 μmol) 2-hydrazino-2-imidazolin hydrobromide is added. After stirring for 4.5 h at room temperature, 1 equivalent each of Wang aldehyde resin and sulfonohydrazide resin are added and stirred for 2 h. Separation of the resin by filtration and concentration of the reaction solution at high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[NH2:22][OH:23]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:22][OH:23])[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(C(=NO)c1ccc(F)cc1)c1ccncc1
Reaction time: 1 h

Procedure:
2-(4-Fluorophenyl)-1-(4-pyridinyl)ethanone (0.1 mol/25.2 g) was suspended in 330 ml of methanol. After addition of sodium acetate (0.44 mol/36.1 g) and hydroxylamine*HCl (0.32 mol/22.0 g), the reaction mixture was heated under reflux with stirring for 1 h. On cooling in an ice bath, the title compound was obtained as a white precipitate. The precipitate was filtered off, washed with H2O and dried over P2O5 under reduced pressure. Yield: 14.3 g (62%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[C:14]([Si:18]([CH3:25])([CH3:24])[O:19][CH:20]1[CH2:23][NH:22][CH2:21]1)([CH3:17])([CH3:16])[CH3:15].CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.CO.O>[C:14]([Si:18]([CH3:25])([CH3:24])[O:19][CH:20]1[CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=2)[CH2:21]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(O[Si](C)(C)C(C)(C)C)C2)cc1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A mixture of 3.0 g (12.4 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1), 2.3 g (12.4 mmol) 3-(tert-butyl-dimethyl-silanyloxy)-azetidine (US2008/214520A1), 4.9 g (97%, 49.6 mmol) NaOtBu, 1.48 g (4.96 mmol) 2-(di-tert-butylphosphino)biphenyl and 1.1 g (1.24 mmol) tris-(dibenzylideneacetone)-dipalladium(0) in 30 mL 1,4-dioxane is stirred for 45 min under microwave irradiation at 80° C. After cooling water and MeOH are added, the mixture is filtered, concentrated in vacuo and directly purified by HPLC (column: XbridgeC18; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17]3[N:18]=[C:19](I)[C:20]4[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:21]=4[N:22]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CN(C=O)C.[Pd]>[CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17]3[N:18]=[CH:19][C:20]4[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[NH:23][C:21]=4[N:22]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(I)c21
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)ncc21

Procedure:
230 mg (0.454 mmol) of 2-[1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were dissolved in 8 ml of absolute DMF, 150 mg of 10% palladium on carbon were added and the mixture was hydrogenated with hydrogen at standard pressure for 3 h. The reaction mixture was filtered through Celite and concentrated. The residue was triturated with 4 ml of acetonitrile, filtered off with suction and dried under high vacuum. This gave 123 mg of the target compound (purity 94%, 67% of theory).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.[CH:34]([C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:40]2[CH:41]=[CH:42][C:37]([CH:34]([CH3:36])[CH3:35])=[CH:38][CH:39]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:27])=[O:28])([CH3:31])([CH3:32])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: CC(C)c1ccc(O)cc1
Product: CC(C)c1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1

Procedure:
The title compound was prepared from 3-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate and 4-isopropylphenol in a similar manner as described for Example 12. 1H NMR (500 MHz CDCl3): δ 7.56-7.50 (m, 2H), 7.48-7.42 (m, 3H), 7.16 (d, 2H), 6.80 (d, 2H), 5.78 (t, 1H), 3.88 (t, 2H), 3.10-3.05 (m, 2H), 2.92-2.82 (m, 1H), 1.85-1.80 (m, 2H), 1.75 (s, 9H), 1.24 (d, 6H); 13C NMR (125 MHz CDCl3): δ 159.8, 156.6, 141.8, 135.4, 131.8, 129.7, 128.8, 127.5, 125.4, 114.4, 107.1, 66.1, 61.7, 42.6, 33.5, 29.0, 27.9, 24.4; Mass Spectrum: M+H+ 457.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:28])[C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[I-].[NH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:28])[C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=4[F:27])[CH:15]=[CH:16][CH:17]=3)=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)[CH:7]=[CH:6][N:5]=1
Reactant: O=C(Nc1cccc(C#Cc2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reaction time: 3 h
Yield: 88.4 %

Procedure:
KOH (1.0 g, 17.4 mmol) was ground to a powder and added to a rt solution of N-{3-[(2-chloro-4-pyrimidinyl)ethynyl]phenyl}-2,6-difluorobenzamide (6.4 g, 17.4 mmol), 1-aminopyridinium iodide (3.85 g, 17.4 mmol), K2CO3 (4.8 g, 34.7 mmol) and DMSO (100 mL) at rt. The reaction was stirred for 3 h and the product crystallized out of the reaction mixture. The reaction was combined with an equal volume of water and the suspension was filtered. The solids were washed with water, then triturated with diethyl ether. The resulting brown solid was dried for 24 h at 60° C. under vacuum to give 7.1 g (89%) of the crude title compound as a brown powder. MS (ESI): M+H=461.99.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[S:10][C:9]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]=2[CH:7]=1)=[O:5].S(=O)(=O)(O)O.P([O-])([O-])(O)=O.[K+].[K+].C(OCC)(=O)C>O>[CH3:14][C:12]1([CH3:15])[CH2:13][C:8]2[C:7]3[CH2:2][CH2:3][C:4](=[O:5])[C:6]=3[S:10][C:9]=2[CH2:11]1
Reactant: CC1(C)Cc2cc(C(=O)CCCl)sc2C1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2sc3c(c2C1)CCC3=O
Temperature: 90 °C
Yield: 37 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with crude 106e (2.86 g, 10.0 mmol presuming quantitative yield) and 98% sulfuric acid. The reaction mixture was heated in a 90° C. oil bath overnight. The reaction mixture was placed into an ice/acetone bath, and a cold (5° C.) solution of dipotassium hydrogen phosphate (105 g, 0.603 mol) in water (300 mL) was added in one portion. The resulting mixture was shaken with ethyl acetate (300 mL) and filtered. The filter cake was washed with ethyl acetate (100 mL). The ethyl acetate layer of the filtrate was separated, dried over sodium sulfate and evaporated under reduced pressure on a rotary evaporator. the resulting residue was purified by flash column chromatography (silica, 80:20 hexanes/ethyl acetate) to afford 106f in 37% yield over two steps (683 mg) as an amorphous brown solid: mp 60-62° C.; 1H NMR (500 MHz, CDCl3) δ 2.92-2.87 (m, 4H), 2.79 (s, 2H), 2.53 (s, 2H), 1.26 (s, 6H); LCMS (ESI+) m/z 207.0 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[CH3:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][NH2:23])=[N:18][CH:17]=[CH:16][N:15]=1>C(O)(C)C>[CH3:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][NH:23][CH2:7][CH:6]([OH:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1nccnc1OCCN
Reactant: Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: Cc1ccccc1OCC(O)CNCCOc1nccnc1C
Reaction time: 24 h

Procedure:
A solution of 4.92 g of 1-(o-methyl-phenoxy)-2,3-epoxypropane and 4.59 g of 2-methyl-3-(2-amino-ethoxy)pyrazine in 150 ml of isopropanol is stirred for 24 hours at about 20° C. and thereafter a further 1.47 g of 1-(o-methyl-phenoxy)-2,3-epoxy-propane are added. After standing for a further 24 hours at about 20° C., the reaction mixture is evaporated under a waterpump vacuum, the residue is dissolved in ether, the ether solution is extracted by shaking with 2 N hydrochloric acid and the combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution and extracted by shaking with ether. The combined ether extracts are washed with water, dried over sodium sulphate and evaporated under a waterpump vacuum. The residue crystallises from methylene chloride/petroleum ether, giving 1-[2-(2-methyl-3-pyrazinyloxy)-ethyl-amino]-3-(2-methyl-phenoxy)-2-propanol; melting point 82°-84° C. The acid fumarate prepared with the calculated amount of fumaric acid crystallises from isopropanol, melting point 140°-141° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[O:8][C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:6]=2[CH:5]=1)([O-])=O>[Ni].C(O)C>[CH:5]1[C:6]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:9]=3[O:8][C:7]=2[CH:16]=[CH:17][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCCC3
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 91.4 %

Procedure:
Potassium t-butoxide (19 g, 1600 mmol) was added in portions to a cooled (2° C.) solution of cycloheptanone oxime (19 g, 150 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 40 minutes and then 1-chloro-4-nitrobenzene (25 g, 160 mmol) in DMF (50 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 2 hours, and then stood at ambient temperature for 16 hours. The reaction mixture poured into water (1600 mL) with stirring. The mixture was stirred for an additional 20 minutes and then allowed to stand at room temperature for 5 hours. The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from hexane provided cycloheptanone O-(4-nitro-phenyl)-oxime (30 g). Cycloheptanone O-(4-nitro-phenyl)-oxime (12 g, 50 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (17 mL) was added. The reaction mixture was heated to reflux for 4 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (7.8 g, 34 mmol). A mixture of 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (5.8 g, 25 mmol) and Raney nickel (-5.6 g wet weight) in ethanol (270 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (gradient elution with 15-25% ethyl acetate-hexanes) to give 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (4.6 g). Mp 98-99° C.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([CH3:28])[CH:2]=[CH:3][C:4]([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C(=O)CCC(=O)O)cc3C2)cc1

Procedure:
Prepared analogously to Example 2 from methyl 4-(2-p-toluenesulphonamido-indan-5-yl)-4-oxobutyrate by hydrolysis with sodium hydroxide.
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH-].[NH4+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=[CH:11][N:10]=1.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[C:27]([Cl:39])[CH:26]=1>>[C:29]([C:28]1[CH:37]=[CH:38][C:25]([NH:24][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH:23]=[CH:22][N:21]=[CH:20]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:26][C:27]=1[Cl:39])(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Clc1ncnc2ccc(-n3ccnc3)cc12
Reactant: Nc1ccc(C(=O)c2ccccc2)c(Cl)c1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Product: O=C(c1ccccc1)c1ccc(Nc2ncnc3ccc(-n4ccnc4)cc23)cc1Cl
Yield: 11 %

Procedure:
Using an analogous procedure to that described in Example 4 except that the reaction product was basified by treatment with a saturated aqueous sodium bicarbonate solution rather than with a concentrated aqueous ammonium hydroxide solution, 4-chloro-6-(1-imidazolyl)quinazoline was reacted with 4-amino-2-chlorobenzophenone to give 4-(4-benzoyl-3-chloroanilino)-6-(1-imidazolyl)-quinazoline in 11% yield, m.p. 220-223° C.; NMR Spectrum: (CD3SOCD3) 7.2 (s, 1H), 7.5-7.8 (m, 6H), 7.9 (s, 1H), 8.0 (d, 1H), (m, 1H), 8.25 (m, 1H), 8.3 (d, 1H), 8.4 (s, 1H), 8.78 (s, 1H), 8.8 (d, 1H), 10.0 (broad s, 1H);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:17]C(=O)C)([O-:3])=[O:2].[OH-].[Na+].Cl.[Cl-].[NH4+]>CO>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH2:17])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
N-(2-nitro-4-phenoxy-phenyl)acetamide (0.67 g, 2.33 mmol) prepared in Step B was dissolved in methanol (5 mL), 6.0N sodium hydroxide (1.5 mL) was added thereto, and the mixture was stirred for 18 h at room temperature. After completion of the reaction, 6.0N aqueous hydrochloric acid solution (1.3 mL) and ammonium chloride solution (100 mL) were added thereto. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and recrystallized from dichloromethane and hexane to give the title compound (521 mg, 2.12 mmol).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH2:11][C:12]([CH3:14])=[CH2:13])[C:8]([OH:10])=[O:9])[CH:2]=1>C(O)C.[Pd]>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=[O:9])[CH:2]=1
Reactant: C=C(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Yield: 100 %

Procedure:
A mixture of 2-biphenyl-3-yl-4-methylpent-4-enoic acid (250 mg, 0.9 mmol), prepared as in Example 2, and 5% Pd/C (50 mg) in 10 ml of ethanol was hydrogenated (40 psi) for 2 hours. The mixture was filtered and the filtrate concentrated to provide 2-biphenyl-3-yl-4-methylpentanoic acid (250 mg, 0.9 mmol). 1H NMR (DMSO-d6): 1.01 (d, 6H), 1.81-1.85 (m, 3H), 3.68 (dd, 1H), 7.08 (d, 1H), 7.24-7.37 (m, 8H). LCMS: 269.1 (M+H+).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:16][CH:15]=[C:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:13]=2>>[Br:9][C:10]1[N:11]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:12]2[C:17]([C:18]=1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:16][CH:15]=[C:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:13]=2
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
NaH (1.4 eq, 60% dispersion in mineral oil) was added to a solution of tert-butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate in DMF (from Step 5, 0.15 M) and the solution stirred at RT for 30 min. Then methyl bromoacetate (1.4 eq) was added and the mixture stirred at RT for 3 h. The solvent was removed in vacuo and the residue taken up in EtOAc. The organic phase was washed twice with aqueous HCl (0.5 N) and then brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by crystallisation (EtOAc/PE) to afford the title compound (80%); MS (ES+) m/z 450 (M+H)+, m/z 452 (M+H)+.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:38](O)(=[O:41])[CH2:39][CH3:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1(/[CH:11]=[C:12]2/[CH:13]([O:22][C:38](=[O:41])[CH2:39][CH3:40])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)O
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of Compound 20b (10.0 mg, 3.50×10−2 mmol), DCC (7.2 mg, 3.50×10−2 mmol), and DMAP (8.5 mg, 6.99×10−2 mmol) in dry CH2Cl2 (4 mL) cooled in an ice-water bath was added propionic acid (3.8 mg, 5.24×10−2 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 8.3 mg (69 percent) of Compound 36: pale yellow oil; Rf=0.43 (20 percent EtOAc in hexane); IR (neat) 2958, 2235, 1726, 1189, 1067 cm−1; 1H NMR (300 MHz, CDCl3) δ8.31 (d, J=7.23 Hz, 1H), 8.01 (d, J=7.56 Hz, 1H), 7.83 (t, J=8.01 Hz, 2H), 7.54-7.46 (m, 3H), 7.45 (s, 1H), 6.24 (s, 1H), 2.52-2.24 (m, 6H), 1.96-1.67 (m, 4H), 1.20 (t, J=7.56 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ174.5, 134.2, 133.0, 132.7, 132.2, 129.7, 129.3, 127.0, 127.0, 126.5, 126.0, 124.2, 123.8, 103.3, 93.6, 81.0, 79.5, 69.4, 28.5, 28.3, 28.2, 22.6, 21.5, 9.8; MS (+CI) m/z (relative intensity) 342 (M+, 5), 269 (100).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[N:10](CC2C=CC(OC)=CC=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[NH:10][C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccccc3)C3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1Cc1ccccc1
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-3-benzyl-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step B (110 mg, 0.24 mmol) in acetonitrile (1.5 mL) was added dropwise a solution of ammonium cerium (IV) nitrate (395 mg, 0.72 mmol) in H2O (1 mL). After 3 h at ambient temperature, the precipitate was isolated by filtration and dried in vacuo to afford the title compound. MS: m/Z=338 (M+1).