Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25](C(OCC4C=CC=CC=4)=O)[C:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=3[C:15]=2[CH3:16])[O:9][CH:10]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=3[C:15]=2[CH3:16])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(-c2oc3cccc(OCCCN(C(=O)OCc4ccccc4)C(C)(C)C)c3c2C)n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1coc(-c2oc3cccc(OCCCNC(C)(C)C)c3c2C)n1

Procedure:
2-{4-[3-(Benzyloxycarbonyl-tert-butyl-amino)-propoxy]-3-methyl-benzofuran-2-yl}-oxazole-4-carboxylic acid ethyl ester (20 mg) in methanol (5 ml) was treated with catalytic amount of 10% palladium on carbon under hydrogen atmosphere at room temperature for 18 hours. After filtration, evaporation and purification by silica gel column chromatography using 10:1 mixture of dichloromethane and methanol as an eluent, 2-{4-[3-(tert-butylamino)-propoxy]-3-methyl-benzofuran-2-yl}-oxazole-4-carboxylic acid ethyl ester was obtained as a white solid (8 mg). FAB-MS: m/z 401.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=O)[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1.O>[C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[S:30])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Solvent: Cc1ccccc1
Solvent: O
Product: S=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Yield: 68.7 %

Procedure:
Compound 12 (48.6 mg, 0.18 mmol) in toluene (2 mL) was treated with Lawesson's reagent (75 mg, 0.18 mmol) at room temperature. The solution was heated at reflux for 2 h, then allowed to cool to room temperature and diluted with water. The mixture was extracted with EtOAc (3×5 mL). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was crystallized (CH2Cl2/hexanes) to give the thioamide 34.4 mg (68%) as a yellow solid. mp 223-226° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.10 (m, 2H), 3.50 (m, 2H), 7.23 (app t, 1H, J=7.8 Hz), 7.57 (m, 1H), 7.61 (m, 3H), 7.69 (m, 2H), 8.19 (d, 1H, J=7.6 Hz), 10.56 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H15N2S: 279.0956, Found: 279.0952; Anal. (C17H14N2S.0.25 H2O) C, H, N, S.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH:23]1([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: IC1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCCC3)CC2)cc1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (12 g, 57.9 mmol) (Acros Organics), powdered potassium carbonate (5.4 g, 39 mmol), iodocyclopentane (7 mL, 60.8 mmol) (Aldrich) and a catalytic amount of 18-crown-6 in acetonitrile (90 mL) was heated at reflux overnight. The mixture was filtered, and the filter cake was washed with acetonitrile. The solvent was evaporated from the combined filtrates and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, evaporated to a yellow solid and dried under vacuum to give 1-cyclopentyl-4-(4-nitrophenyl)piperazine) (6.6 g, 41%)
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S]>>[SH:2][C:1]1[S:3][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: S=C=S
Reactant: Nc1ccccc1
Agent: [S]
Product: Sc1nc2ccccc2s1

Procedure:
In a process for purifying crude molten 2-mercaptobenzothiazole, prepared by reacting aniline carbon disulfide and sulfur at elevated temperature and pressure, in which the purification includes the steps of separating dissolved alkali metal salt of 2-mercaptobenzothiazole from undissolved impurities, treating the dissolved alkali metal salt of 2-mercaptobenzothiazole with an excess of a non-oxidizing mineral acid to precipitate a slurry of purified 2-mercaptobenzothiazole, separating the purified 2-mercaptobenzothiazole solids from the slurry to obtain 2-mercaptobenzothiazole solids, washing the solids with water, and drying the purified 2-mercaptobenzothiazole, the improvement comprising; forming said dissolved alkali metal salt at 2-mercaptobenzothiazole and said dissolved impurities by the steps of
Reaction SMILES: NC1C=CC(O)=C(F)C=1.FC1C=CC(CC(SC#N)=O)=CC=1.[F:23][C:24]1[CH:25]=[C:26]([NH:43][C:44]([NH:46][C:47](=[O:56])[CH2:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[S:45])[CH:27]=[CH:28][C:29]=1[O:30]C1C2=C(C)C(OC)=CN2N=CN=1.CCOC(C)=O>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([NH:43][C:44]([NH:46][C:47](=[O:56])[CH2:48][C:49]2[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=2)=[S:45])[CH:27]=[CH:28][C:29]=1[OH:30]
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Agent: N#CSC(=O)Cc1ccc(F)cc1
Agent: Nc1ccc(O)c(F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 4-amino-2-fluorophenol (50 mg, 0.3 mmol, Indofine Chemical Co.) in CH2Cl2 (5 mL) was added a 0.25 M solution of 2-(4-fluorophenyl)-1-thiocyanatoethanone (prepared using a similar procedure for the synthesis of Compound A of Example 2) in EtOAc (1.6 mL, 0.4 mmol). The reaction was stirred at room temperature for 20 minutes, concentrated in vacuo and purified by silica gel flash chromatography (eluted with 1–25% EtOAc/CH2Cl2) to give the title compound (100 mg, 95%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N:11]([CH3:22])[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:14]
Reactant: CI
Reactant: COC(=O)c1cc(NS(=O)(=O)c2cccs2)c(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N(C)S(=O)(=O)c2cccs2)c(C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of methyl 5-methyl-4-[(2-thienylsulfonyl)amino]thiophene-2-carboxylate (35.7 g) in N,N-dimethylformamide (200 mL) was slowly added sodium hydride (60%, oily, 5.2 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (8.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give methyl 5-methyl-4-[methyl(2-thienylsulfonyl)amino]thiophene-2-carboxylate (37.5 g, yield 99%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])([F:16])[C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]#[N:15])=[CH:9][CH:8]=2.I[CH3:19].O>CN(C=O)C>[CH3:19][N:6]1[C:7]2[C:12](=[CH:11][C:10]([C:14]#[N:15])=[CH:9][CH:8]=2)[CH:13]=[C:5]1[C:4]([F:3])([F:16])[F:17]
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 135.9 %

Procedure:
Sodium hydride (60% in mineral oil) (76 mg, 1.903 mmol) was added to 2-trifluoromethyl-1H-indole-5-carbonitrile (Intermediate 3, 200 mg, 0.952 mmol) stirred in DMF (5 ml) under argon at room temperature. The reaction mixture was stirred at room temperature for 30 min and iodomethane (0.119 ml, 1.903 mmol) was then added. The reaction mixture was left to stir for a further 1 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic extract was washed with 1:1 water:Brine (50 ml×2), dried (MgSO4), filtered and the solvent removed to give the title compound (290 mg) which was then used in the next reaction without further purification;
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34]O)=[NH:33])=[CH:30][N:29]=1>>[F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:34]=[C:32]([C:31]4[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=4)[N:33]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(N)nc1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) (186 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (113 mg, 46%). MS (ISP) 488.1 [(M+H)+]; mp 231° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].CON(C)[C:18]([C:20]1[S:24][C:23]([CH3:25])=[N:22][C:21]=1[CH3:26])=[O:19]>C1COCC1>[CH3:25][C:23]1[S:24][C:20]([C:18]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:19])=[C:21]([CH3:26])[N:22]=1
Reactant: CON(C)C(=O)c1sc(C)nc1C
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2cncn2C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (390 mg, 2.42 mmol) was added THF (8 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropyl magnesium chloride-LiCl complex (1.3 M in THF, 2.5 mL, 3.25 mmol) which resulted in a white suspension. The mixture was stirred at 0° C. for 30 min, then a THF solution (2 mL) of N-methoxy-N,2,4-trimethylthiazole-5-carboxamide (550 mg, 2.75 mmol, Intermediate 41, step a) was introduced and the mixture was allowed to warm to room temperature. After 3 hours at room temperature the mixture was heated to 50° C. for 18 hours, followed by quenching with NH4Cl solution. The aqueous portion was extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (25-50% EtOAc-DCM increasing gradient to 5% MeOH-DCM) provided the title compound as an amber solid.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:7])=[CH:4][CH:3]=1.Cl>>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:6](=[O:7])[C:5]2[CH:27]=[CH:28][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=1
Reactant: O=C(c1ccc(O)cc1)c1c(Cc2ccc([N+](=O)[O-])cc2)oc2ccccc12
Agent: Cl
Product: Nc1ccc(Cc2oc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Reaction time: 12 h

Procedure:
3-(4'-Hydroxybenzoyl)-2-(4'-nitrobenzyl)benzofuran (37.3 g., 0.1 mol.) is added in small portions to 56.4 g. (0.25 mol.) of stannous chloride dihydrate in 70 ml. of concentrated hydrochloric acid. The reaction mixture is heated at 50° for 3 hours, then stirred at 25° for 12 hours. Cooling (ice bath) enhances precipitation of the product salt which is collected by filtration and dissolved in water. The aqueous solution is made basic by addition of 10% aqueous sodium hydroxide and extracted with chloroform. The extracts are dried (MgSO4) and concentrated to give 2-(4'-aminobenzyl)-3-(4'-hydroxybenzoyl)benzofuran.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7](C(OC)=O)[CH2:6][C:5]=2[O:4][N:3]=1.[BrH:15].[K+].[Br-].CO>C(O)(=O)C>[Br-:15].[OH:1][C:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[O:4][NH+:3]=1
Reactant: Br
Reactant: COC(=O)N1CCc2c(O)noc2C1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Oc1[nH+]oc2c1CCNC2

Procedure:
A solution of methyl 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5, 4-c]-pyridine-6-carboxylate (309 mg; 1.6 mmol) in a solution of hydrogen bromide in glacial acetic acid (3 ml; 43%) was refluxed for 15 minutes. Upon evaporation to dryness in vacuo the residue was treated with the same reagent (3 ml) for further 15 minutes. Evaporation of the reaction mixture to dryness in vacuo and recrystallization (methanol-ether) of the residue gave Ia (salt) (193 mg; 56%) as faintly reddish crystals, m.p. 162-163° C. (decomp.). IR (KBr): 3700-3300 (m), 3070 (s), 3000-2300 (several bands, m-s), 1670 (m), 1580 (m), 1525 (s), 1505 (w) cm-1. UV (methanol): <210 nm. 1H NMR [D2O (sodium 3-(trimethylsilyl) propanesulfonate was used as an internal standard)]: δ4.77 (ca. 5 H, s), 4.43 (2 H, t, J 1 Hz), 3.7- 3.4 (2 H, q, J 6 and 7 Hz), 3.0-2.7 (2 H, t).
Reaction SMILES: B(F)(F)F.CCOCC.[BH4-].[Na+].[CH3:12][N:13]([CH3:30])[CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:12][N:13]([CH3:30])[CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CN(C)CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCN1CCOc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Boron trifluoride etherate (2 ml, 16.2 mmol) was added dropwise to a suspension of sodium borohydride (0.46 g, 12 mmol) in dry THF (30 ml) at 0° C., under argon. After 1 hr, a solution of 4-(2- dimethylaminoethyl)-6-nitro-2H-1,4-benzoxazine-3(4H )-one (D1, 1.08 g, 4 mmol) in dry THF (20 ml) was added. The reaction mixture was heated under reflux for 2 hr, then cooled in ice. Aqueous NaHCO3 was added dropwise until effervescence ceased, then the solvent was removed under reduced pressure and the residue dissolved in a mixture of EtOH (10 ml) and 5N HCl (10 ml) and heated under reflux for 45 minutes. After cooling, the solvent was removed under reduced pressure. The residue was treated with satturated K2CO3 solution to pH 8, then extracted with EtOAc. The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound (0.94 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: Cc1ccc(N=C=S)c(C)c1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2ccc(C)cc2C)C1=S
Yield: 43.6 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2,4-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.8 g) as a light peach solid, m.p. 161°-162° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.63; H, 6.45; N, 11.17. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1
Yield: 60 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 4-methoxy-benzylamine according to the GPA affording 24.7 mg (60%) of a red powder. Rt=4.97 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH2:12]O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:16].O>C(OC(C)C)(C)C>[Br:16][CH2:12][C:11]([CH3:14])=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: BrP(Br)Br
Reactant: CC(=Cc1ccc(C(C)C)cc1)CO
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(=Cc1ccc(C(C)C)cc1)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2-methyl-2-propen-1-ol synthesized in Reference Example 103 (6.30 g, 33.1 mmol) in isopropyl ether (50 mL) was added phosphorus tribromide (5.98 g, 22.1 mmol) with ice-cooling and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the mixture was extracted with isopropyl ether. The organic layer was washed with water and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain the oily title compound 7.63 g (yield 91%)
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[NH3:23]>CN(C)C=O.[Cu-]=O>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:23])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: N
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(N)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 110 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see example 4) (2.71 g, 7.34 mmol) and copper(I) oxide (0.247 g, 1.726 mmol) in N,N-dimethylformamide (DMF) (5 mL) was treated with NH3 (35% w/w in water) (5 mL, 258 mmol) and the resulting mixture was stirred at 110° C. for 5 h under microwave irradiation then cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and AcOEt and the layers were separated. The aqueous phase was extracted with AcOEt (2×50 mL) and the combined organic phases were dried over MgSO4 then concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 10 to 100% AcOEt in Hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-amino-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (1.91 g, 6.25 mmol, 85%) as an orange foamy solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=[C:4]([O:25][Si](C(C)(C)C)(C)C)[CH:3]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(C1C2OC=CC=2C=CC=1)=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1.C1COCC1.C(OCC)C>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[O:9][C:10]3[C:2]([CH:33]=[CH2:34])=[CH:3][C:4]([OH:25])=[CH:5][C:6]=3[CH:7]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc3cc(O[Si](C)(C)C(C)(C)C)cc(Br)c3o2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: C=Cc1cccc2ccoc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: C=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
To a solution of 66 (0.48 g, 0.9 mmol) in xylene was added tributyl vinyl tin (0.28 g, 0.9 mmol) and tri-(o-tolyl)phosphine (0.055 g, 0.18 mmol). This mixture was purged with nitrogen for 15 minutes. Then palladium (II) chloride was added and there action was heated at 130° C. for 2 hours. The reaction was filtered and the solvent removed in vacuo. The residue was used in the next step without further purification. To a solution of 5-(tert-butyl-dimethyl-silanyloxy)-2-[4-tert-butyl-dimethyl-silanyloxy)-phenyl]-7-vinyl-benzofuran (0.4 g, 0.9 mmol) in THF (10 mL) was added 1.0M tetrabutyl ammonium fluoride (1.8 mL, 1.8 mmol) and the reaction mixture was stirred at room temperature 20 minutes. The reaction was diluted with ethyl ether and washed twice with water. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The product was purified via flash chromatography, eluting with 50% ethyl acetate in hexane, to give 0.19 g of 2-(4-hydroxy-phenyl)-7-vinyl-benzofuran-5-ol 67: Mp=182–184° C.; 1H NMR (DMSO-d6) δ 9.86 (s, 1 H), 9.20 (s, 1 H), 7.73 (d, 2 H, J=8.6 HZ), 7.06 (s, 1 H), 6.89 (d, 2 H, J=8.8 Hz), 6.92 (dd, 1 H, J=16.7 Hz, 11.3 Hz), 6.84 (d, 1 H, J=2.3 Hz), 6.76 (d, 1 H, J=2.3 Hz), 6.21 (dd, 1 H, J=17.8 Hz, 1.2 Hz), 5.54 (dd, 1 H, J=11.3 Hz, 1.2 Hz); MS 253 (M+H)+.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.BrC1C=CC(C#N)=CC=1.[OH-:19].[Cs+]>>[OH:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: [OH-]
Agent: N#Cc1ccc(Br)cc1
Agent: [Cs+]
Product: N#Cc1ccc(O)cc1

Procedure:
Following general operating mode A, 4-iodobenzonitrile or 4-bromobenzonitrile (229 mg or 182 mg, 1.0 mmol) were reacted at respectively 110° C. or 130° C. with cesium hydroxide to afford the expected product in the form of a white solid at respective yields of 91% and 94% (eluent: ethyl acetate/heptane 20:80).