Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Br[C:13]1[CH:14]=[CH:15][C:16]([O:33][CH2:34][CH3:35])=[C:17]([C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)[CH:18]=1.O.O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na].[Na].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.[Cl-].[Zn+2].[Cl-].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.CO>[CH2:34]([O:33][C:16]1[CH:15]=[CH:14][C:13]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)=[CH:18][C:17]=1[C:19]1[NH:20][C:21](=[O:32])[C:22]2[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:24]=1)[CH3:35]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: Cn1ccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(-c4nccn4C)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 9.6 ml, 0.0153 mol) was added to a stirred solution of 1-methyl-imidazole (0.628 g, 0.0077 mol) in dry tetrahydrofuran (10 ml) at −78° C., and the resulting solution stirred for 0.25 hours. A solution of anhydrous zinc chloride (2.08 g, 0.0153 mol) in dry tetrahydrofuran (15 ml) was added, the mixture allowed to warm to room temperature, then 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (1.0 g, 0.0026 mol) and tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.031 mol) were added and the mixture heated under reflux for 18 hours. A further quantity of anhydrous zinc chloride (2.08 g, 0.0153 mol) was added and the resulting mixture heated under reflux for a further 60 hours, then cooled, methanol (2 ml) was added and the solvent removed by evaporation under vacuum. The residue was heated with a solution of disodium ethylenediaminetetraacetic acid dihydrate (23.0 g, 0.0618 mol) in water (100 ml) to 100° C. for 0.2 hour, then the resulting solution basified to pH 8 with saturated aqueous sodium carbonate solution and extracted with dichloromethane (6×100 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum to give a yellow solid, purification of which by chromatography on silica gel (13 g), using a methanol-dichloromethane elution gradient (0-3% methanol), followed by crystallization from ethyl acetate, gave the title compound as an off-white solid (0.542 g, 53%), m.p. 199-202° C. Found: C,64.45; H,6.27; N,21.56. C21H24N6O2 requires C,64.27; H,6.16; N,21.42%.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[CH3:21]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:18])([CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: CI
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a stirred solution of 10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 127; 9.67 g, 32.8 mmol) in DMA (710 mL) under nitrogen was added methyl iodide (2.25 mL, 36.08 mmol). The mixture was cooled in ice/water to 2.5° C. Sodium hydride (60% dispersion in mineral oil, 1.45 g, 36.08 mmol) was added in one portion. A small exotherm to 4° C. was observed. The reaction mixture was stirred on an ice/water bath for 1 hour, and then stirred at room temperature overnight. Solvent was removed in vacuo and the light-brown liquid residue was treated with water. This afforded a solid, which was filtered off and washed with water. The solid material was dissolved in DCM (200 mL) and the solution dried using MgSO4, filtered and evaporated to give an off white solid which was purified on a 330 g Si column (Companion). loading as a solution in DCM (60 mL) The column having been equilibrated with 30% Ethyl Acetate in isohexane, and eluted with 30% Ethyl Acetate in isohexane for the first 5 minutes and then with a linear gradient slowly rising to 100% Ethyl Acetate. Product containing fractions were combined and evaporated to dryness to give the title compound as a white solid (9.29 g, 92%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10])=[CH:6][C:5]([NH:14][C:15]([N:17]2[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:18]2[C:23](O)=[O:24])=[O:16])=[C:4]([F:26])[CH:3]=1.ON1C(=O)CCC1=O>C(#N)C>[Cl:13][CH2:12][S:9]([NH:8][C:7]1[CH:6]=[C:5]([N:14]2[C:23](=[O:24])[C@H:18]3[CH2:19][C@@H:20]([OH:22])[CH2:21][N:17]3[C:15]2=[O:16])[C:4]([F:26])=[CH:3][C:2]=1[Cl:1])(=[O:11])=[O:10]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C1[C@H]2C[C@@H](O)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 116.8 %

Procedure:
To a stirred solution of the title compound of Step F (2.7 g, 5.4 mmol) and N-hydroxysuccinimide (0.621 g, 5.4 mmol) in acetonitrile (50 mL) was added a solution of N,N-dicyclohexylcarbodiimide (1.14 g, 5.4 mmol) in acetonitrile (30 mL) over 30 minutes at 0 to -5° C. The reaction was stirred at room temperature for 14 h. The by-products were removed by filtration and the solvent was evaporated under reduced pressure to yield the title compound of Step G (2.6 g, quantitative yield) as a crude product melting at 198-200° C. 1H NMR (Me2SO-d6) δ 10.2 (br s, 1H), 7.8-7.7 (d, 1H), 7.5-7.4 (d, 1H), 5.2-5.1 (br s, 1H), 5.1-5.0 (s, 2H), 4.5 (m, 1H), 4.34.2 (m, 1H), 3.1 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.FC(F)(F)S(O[Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])(=O)=O.CC1C=CC=C(C)N=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([O:16][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:15]=1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxybiphenyl-2,4-diol (10.6 g) in toluene (80 mL) were added triisopropylsilyl trifluoromethanesulfonate (18 mL) and 2,6-dimethylpyridine (8.0 mL) at −15° C., and the mixture was stirred for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.5 g) as a pale-yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.CC(C)CC=O.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([N:15]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CCC(C)C)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)Nc1cccc(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, 3-methylbutanal and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.O1CCCC1>[Pd].C(O)C>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:5]3[C:4]4[CH:3]=[CH:2][N:12]=[CH:11][C:10]=4[O:9][CH2:8][CH2:7][N:6]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccncc1OCC2
Reaction time: 3 h

Procedure:
A mixture of 10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (82.7 mg, 0.250 mmol), palladium on carbon 10% (0.1:0.9, Palladium:carbon black, 83 mg) and triethylamine (0.104 mL, 0.750 mmol) in 5.0 ml of ethanol and 5.0 ml of tetrahydrofuran (5.0 mL, 62 mmol) was hydrogenated at 1 atm for 3 hours. The catalyst was filtered out, the filtrate concentrated, the residue purified by RP HPLC, acetonitrikle gradient to give 233. Yield 32 mg (43%). MS(ESI+): 297.2. 1H NMR (500 MHz, DMSO) δ 8.40 (s, 1H), 8.30 (d, J=5.2, 1H), 8.25 (d, J=5.2, 1H), 8.08 (s, 1H), 7.94 (s, 1H), 5.87 (dt, J=13.0, 6.6, 1H), 4.60 (dd, J=13.1, 5.5, 4H), 1.49 (d, J=6.6, 6H).
Reaction SMILES: COC1CCCC1.[C:8]1([CH3:20])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16](O)([CH3:18])[CH3:17]>C1COCC1>[CH3:18][C:16]([C:9]1[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH3:20])=[CH2:17]
Reactant: Cc1cc(C)c(C(C)(C)O)c(C)c1
Solvent: COC1CCCC1
Solvent: C1CCOC1
Product: C=C(C)c1c(C)cc(C)cc1C
Yield: 66.8 %

Procedure:
The same experiment as in Example 4 was carried out, except for using a mixed solvent of CPME and THF (1:1 by volume) instead of 50 ml of CPME. The resulting reaction mixture was analyzed by gas chromatography to confirm that 2-mesityl-2-propanol and α-methyl-2,4,6-trimethylstyrene were obtained in a yield of 66.8% and 14.7%, respectively.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:13](=O)(O)[O-].[Na+]>Cl.CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2[nH]ccc2c1
Yield: 38.6 %

Procedure:
A mixture of 1.00 g (6.21 mmol) of 5-indolecarboxylic acid and 50 ml of 10% hydrogen chloride/methanol was refluxed for 2 hours. The reaction mixture was then poured onto ice water followed by neutralization with sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 0.42 g (38.6%) of methyl 5-indole-carboxylate.
Reaction SMILES: [N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O.N1C=CN=N1.C([O-])([O-])=O.[K+].[K+].[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[CH:30]=[C:31]([N+:35]([O-])=O)[CH:32]=[CH:33][CH:34]=1.NC1C=CC=CC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>S1(CCCC1)(=O)=O.C1COCC1.O>[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=1)[NH2:35]
Reactant: O=[N+]([O-])c1cccc(-c2ncco2)c1
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(-c2ncco2)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-(2-oxazolyl)aniline to generate the title compound. The 3-(2-oxazolyl)aniline was prepared by treating 3-nitrobenzoyl chloride sequentially with 1,2,3-triazole at 140° C. in sulfolane containing K2CO3 to generate 3-(2-oxazolyl)nitrobenzene which was reduced to the desired aniline with Na2S2O4 in THF/H2O at 90° C.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[C:22]1([NH:28][N:29]=[CH:12][C:11]2[CH:14]=[CH:15][C:8]([N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: NNc1ccccc1
Solvent: CO
Product: C(=NNc1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of 4-(diphenylamino)benzaldehyde (10 g, 0.037 mol) and 300 ml of methanol was added to 500 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was mildly heated by a heating mantle until all solid entered into solution. Then a solution of N-phenylhydrazine (5.94 g, 0.055 mol, from Aldrich, Milwauke, Wis.) in 50 ml of methanol was added. The reaction mixture was refluxed for 0.5 hour and then cooled to room temperature. The yellow precipitated product was filtered off, washed with a large amount of methanol, and dried to yield 11.7 g (86.7%) of 4-(diphenylamino)benzaldehyde N-phenylhydrazone. The melting point was found to be 168–169° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 6.55–7.64 (m, 21H, Ar, ═CH, —NH). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(N—H) 3294, ν(arene C—H) 3026, ν(C═C in Ar) 1595; 1489, ν(C—N) 1282; 1257, γ(Ar) 750; 731. The mass spectrum of the product was characterized by the following mass peaks (m/z): 364 (100%, M+1), 314, 223, 159.
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].[CH2:17]([O:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13].[CH2:17]([O:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]
Reactant: CC[Mg]Br
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: CCCOCCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 50 ml of a dipropyl ether (chain ether solvent) solution containing 0.065 mol of ethyl magnesium bromide was charged to the reaction vessel. Meanwhile, 0.060 mol of bromopentafluorobenzene and 20 ml of dipropyl ether (chain ether solvent) were charged to the dropping funnel. Then, the dipropyl ether solution of bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 1 hour at room temperature, and the reaction solution was stirred for 2 hours at room temperature. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a colorless dipropyl ether solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 94.6 mol % based on bromopentafluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.[OH-].[NH4+:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH2:13])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(Cl)nc1

Procedure:
2-Chloro-5-chlorosulfonylpyridine (2.84 g, 0.0134 mole) was added to concentrated ammonium hydroxide (50 ml) and the mixture was boiled. After adding more concentrated ammonium hydroxide (50 ml), and extending boiling until the reaction volume was approximately 50 ml, the reaction mixture was cooled in an ice bath to cause precipitation of the product. The solid was collected by filtration, washed with water and air dried; yield, 2.17 g (84 percent), m.p. 153° to 155° C. A melting point of 155° to 156° C. was observed after recrystallization from water.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[Na+].Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=[N+]([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCCCCC
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reaction time: 60 h
Yield: 36.8 %

Procedure:
The bi-phasic mixture of 3,5-dimethylphenol (25 g, 0.20 mol) and sodium nitrate (17.4 g, 0.20 mol) in a 1:1 mixture of ether-water (800 ml) containing 40 ml of concentrated HCl was vigorously stirred for several hours. n-Bu4NHSO4 (3.4 g, 0.01 mol) and additional conc. HCl (40 ml) were added and stirring continued for 60 hrs. The reaction mixture was extracted with ether (×2). The combined ether extracts were washed with 1.0N HCl, brine and dried over anhydrous Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 99:1 to 40:60) on silica gel gave, after trituration with hexane, 12.3 g of the title compound of this step as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC(C(CCC(O)=O)=O)=CC=2)C=CC=CC=1>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:10]([CH2:13][CH2:14][CH2:15][C:16]3=[O:18])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccc(-c2ccccc2)cc1
Agent: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Product: O=C1CCCc2ccc(-c3ccccc3)cc21
Yield: 30 %

Procedure:
4-(4'-Biphenylyl) butanoic acid (80g, 0.333 mole m.p. 116° C prepared by the Clemmensen reduction of 3-(4'-biphenylcarbonyl) propanoic acid) was cyclized with 85% polyphosphoric acid as described in example 8(a) to give 20.98g (30%) of the tetralone m.p. 67° C after recrystallisation from 40-60 petrol. (Found; C, 86.30; H, 6.53, C16H14O requires; C, 86.45; H, 6.35%).
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH2:10]([NH:17][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([OH:1])[CH2:3][CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CC1(O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(O)CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a mixture of 4-hydroxy-4-methylcyclohexanone (4.1 g, 32.0 mmol) and benzyl amine (6.8 g, 64.0 mmol) in 1,2-dichloroethane (120 mL) was added acetic acid (3.84 g, 64.0 mmol). After the resulting mixture was stirred at RT for 2 hours, the mixture was added NaBH(OAc)3 (13.6 g, 64.0 mmol). The resulting mixture was then stirred at RT overnight. After the reaction was completed, the mixture was basified to pH 11 by addition of 2 N NaOH. The separated organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (MeOH:DCM=3:100 to 1:10) to afford 4-(benzylamino)-1-methylcyclohexanol as a white solid (5.7 g, yield: 80.0%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[N:11]=1>CN(C=O)C>[Br:1][C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[N:11][C:12]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(Cl)n1
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
N-bromosuccinimide (16.45 g; 92.41 mmol; 1.10 eq.) was added portionwise to a solution of 2-amino-6-chloropyridine (10.80 g; 84.01 mmol; 1.0 eq.) in DMF (200 mL) at rt. The reaction mixture was stirred at rt for 2 hours. Solvents were removed under reduced pressure and the residue was taken up in EtOAc and aqueous ammonia. The organic phase was washed again with aqueous ammonia and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The black solid obtained was washed with pentane and dried under vacuum to give the title compound as a beige powder (12.5 g, 72%). HPLC, Rt: 2.81 min. (purity 95.8%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[Br:9]Br.C(N(CC)CC)C>CO.O1CCCC1>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([Br:9])[C:3]1=[O:8]
Reactant: BrBr
Reactant: CN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
To N-methylmaleimide (0.5 g, 4.5 mmol) in methanol (10 mL) was added bromine (232 μL, 4.5 mmol) dropwise in methanol (5 mL). The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed in vacuo and dissolved in tetrahydrofuran (20 mL). Triethylamine (815 μL, 5.9 mmol) in tetrahydrofuran (5 mL) was added over 5 minutes, whereupon a precipitate formed. The reaction mixture was stirred for 24 hours. The solid was filtered off and washed with tetrahydrofuran (50 mL). Purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a pale yellow powder (563 mg, 2.96 mmol) in 66% yield. δH (500 MHz, CDCl3) 6.90 (s, 1H, H-3), 3.09 (s, 3H, H3-6); δC (125 MHz, CDCl3) 168.6 (C═O), 165.4 (C═O), 131.9 (C3), 131.4 (C2), 24.7 (C6); IR (solid, cm−1) 3106 (s), 1708 (s); MS (CI+) m/z, (relative intensity): 192 ([81M+H], 99), 190([79M+H], 100); Exact mass calcd for [C5H4O2N79Br]+H requires 189.9504 Found 189.9505 (CI+); m.p: 77-79° C.; UV (Acetonitrile) ε209=17100, ε238=13200, ε299=290 cm−1M−1 d3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:16][CH:15]=[CH2:14])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: -20 °C
Yield: 31.5 %

Procedure:
A solution of 3,4-dichlorophenyl acetonitrile (200 g, 1.075 mol) in dry tetrahydrofuran (400 ml) was added dropwise, over one hour to sodium hydride 60% w/w dispersion in oil (32.26 g, 1.075 mole) in dry tetrahydrofuran (400 ml) at 0° C. under nitrogen. After a further thirty minutes the solution was cooled to -20° C. and a solution of allyl bromide (92.9 ml, 1 mol equivalent) in tetrahydrofuran (200 ml) was added, the mixture allowed to warm to room temperature and stirred for fourteen hours. Saturated brine (600 ml) was added and the mixture extracted with dichloromethane (2×600 ml). The organic layers were combined, dried over magnesium sulphate, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with a solvent gradient of ethyl acetate/hexane to provide the title compound as an oil (71.3 g). TLC Rf=0.71 (silica, diethylether:hexane, 1:1 by volume). 1H-NMR (CDCl3): δ=2.6-2.75(m,2H), 3.85(t,1H), 5.1-5.25(m,2H), 5.7-5.9(m,1H), 7.2-7.25(m,1H), 7.5-7.55(m,2H) ppm.