Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:18]1([NH:24][N:25]=[CH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: NNc1ccccc1
Solvent: CO
Product: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21

Procedure:
9-Ethylcarbazole-3-carbaldehyde (10 g, 0.045 mol, from Aldrich, Milwaukee, Wis.) was dissolved in 300 ml of methanol under mild heating. Then, a solution of 7.25 g (0.067 mol) of N-phenylhydrazine (obtained from Aldrich) in methanol was added. The reaction mixture was refluxed for 2 hours. Yellowish crystals were separated by filtration, washed with a large amount of methanol and dried. The yield of the product, 9-ethyl-3-carbazolecarboxaldehyde N-phenylhydrazone, was 13.12 g (92%). The product had a melting point of 136-137° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 1.34 (t, J=7.0 Hz, 3H, CH3); 4.23 (q, J=7.0 Hz, 2H, CH2); 6.90-7.64 (m, 8H, Ar); 7.60 (s, 1H, Ar); 7.81 (dd, 1H, Ar); 8.08 (d, 2H, Ar); and 8.15 (d, 1H, ═CH). The infrared absorption spectrum of the product was characterized by the following the following absorption frequencies (KBr windows, in cm−1): ν(N—H) 3306, ν(C—H) 2972, ν(arene C—H) 3051, ν(C═C, C—N in Ar) 1602; 1494; 1475; 1237, ν(C—N) 1256, γ(Ar) 815; 747; 731. The mass spectrum of the product was characterized by the following ions (in m/z): 314 (90%, M+1); 222 (100%, H5C2-C12H7N—CH═NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 0 °C
Yield: 94.8 %

Procedure:
A solution of 6-bromo-naphthalen-2-ol (18.0 g, 80.7 mmol), t-butyldimethylsilyl chloride (14.6 g, 96.8 mmol), triethyl amine (12.3 g, 121.0 mmol), and DMAP (0.75 g) in THF (400 mL) was stirred at room temperature overnight. The reaction was taken up in ethyl acetate and washed with 1N HCl (2×) and brine, dried over magnesium sulfate, and concentrated to give an oil. The product was crystallized from acetonitrile cooled to 0° C. to give (6-Bromo-naphthalen-2-yloxy)-tert-butyl-dimethyl-silane (25.8 g, 95%) as an off-white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:30](Cl)=[O:31])[CH2:24][CH2:23]1.C1(C(C2CC2)OC2C=CC=CC=2C(Cl)=O)CC1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:30]([NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]3[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[O:31])[CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:39][CH2:40]2)[CH2:24][CH2:23]1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccccc1OC(C1CC1)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Reaction time: 16 h

Procedure:
590 mg of (±)-acetic acid (1RS,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound B1) are dissolved in a mixture of 6 ml of methylene chloride and 1.5 ml of pyridine and 10 mg of 4-dimethylaminopyridine are added. A solution of 595 mg of 3,4-dicyclopropylmethoxybenzoyl chloride in methylene chloride is added dropwise and the mixture is stirred for 16 h. Further 140 mg of dicyclopropylmethoxybenzoyl chloride and 10 mg of 4-dimethylaminopyridine are added to complete the reaction. The solvents are removed and the residue is purified by chromatography on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 5/4/1 as eluent. After concentration of the corresponding eluate fractions, 630 mg (59% of theory) of the title compound are obtained as a colourless foam.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:12][C:13]1[S:16][N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-fluorobenzamidine hydrochloride (0.385 g) in DCM (5 mL) was added perchloromethyl mercaptan (0.219 mL). The resulting mixture was cooled to 0° C., treated with 6 N NaOH (2 mL) and stirred for 30 min. The resulting mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was dried (MgSO4) and concentrated. Chromatography of the residue (0-20% EtOAc-hexanes) gave the title compound as a yellow-orange solid (0.43 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[C:11]=2[CH:10]=[CH:9][N:8]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:17]([C:12]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: NCCCCN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 62 %

Procedure:
In 200 ml of chloroform was dissolved 8.8 g of 1,4-diaminobutane, and to the solution was added dropwise 100 ml of a chloroform solution containing 4.55 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and then the reaction solution was extracted with a 10% aqueous hydrochloric acid solution. The pH of the aqueous layer was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The chloroform layer extracted was washed with water and dried with anhydrous potassium carbonate. Then the chloroform was distilled from the chloroform layer, and the residue obtained was subjected to a column chromatography [silica gel: 200 g; developing solvent: 2% methanol/chloroform (volume ratio)] to give 3.46 g of N-(4-aminobutyl)-5-isoquinolinesulfonamide, i.e., Compound (3) as an oily substance in a yield of 62%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>C1(C)C=CC=CC=1.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>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([CH:16]=[CH2:17])[N:3]=[C:4]([CH3:15])[N:5]=2)[N:9]=1
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1

Procedure:
A slurry of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (2-2, 800 mg, 3.58 mmol, 1.0 eq.), tributyl(vinyl)tin (1.358 mL, 4.65 mmol, 1.3 eq.) and tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.179 mmol, 0.050 eq.) in toluene (20 mL) was heated at 110° C. for 3 hours. Toluene was removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (2-3) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.64 (s, 1H), 6.77 (m, 1H), 6.53 (d, 1H, J=17 Hz), 5.73 (d, 2H, J=11 Hz), 2.92 (s, 3H), 2.72 (s, 3H), 2.42 (s, 3H). LRMS m/z (M+H) 216.2 found, 216.1 required.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[CH:7]=1.[CH3:16]O>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[C:8]([Cl:15])[CH:7]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1Cl
Temperature: 60 °C

Procedure:
Thionyl chloride (1.64 ml) was added dropwise to a suspension of 4-bromo-2-chlorobenzoic acid (6.92 g) in methanol, and heated to 60° C. for 2 hours. The solvent was removed in vacuo, the residue redissolved in ethyl acetate, and washed sequentially with 0.5 N sodium hydroxide (2×), water, and brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent removed in vacuo to afford the title compound (7.8 g). 1H NMR (300 MHz), (DMSO-d6) δ: 3.87 (s,3H), 7.68-7.9 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-hydroxyphenyl)cyclohexanone (1 g, 5.26 mmol) in DMF (50 ml) was added cesium carbonate (3.00 g, 9.20 mmol) followed by methyl iodide (0.411 ml, 6.57 mmol). The reaction was stirred at room temperature for 1 hour and then diluted with ethyl acetate (100 mL), washed with water (3×50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 100% EtOAc/hexanes afforded 4-(4-methoxyphenyl)cyclohexanone. 1H NMR (CDCl3, 500 MHz) δ 7.16 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.99 (m, 1H), 2.45-2.55 (m, 4H), 2.16-2.23 (m, 2H), 1.86-1.96 (m, 2H).
Reaction SMILES: O.[Na].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][C:21]#[N:22])[CH:16]=3)[C:11]2=[O:23])=[CH:7][CH:6]=1.Br[CH2:27][CH2:28]Br.C(OC(=O)C)C>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4([C:21]#[N:22])[CH2:28][CH2:27]4)[CH:16]=3)[C:11]2=[O:23])=[CH:7][CH:6]=1
Reactant: BrCCBr
Reactant: COc1ccc(CN2CCc3cc(CC#N)ccc3C2=O)cc1
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3cc(C4(C#N)CC4)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a suspension of sodium hydrate (0.228 g, 60%, 5.72 mmole) in 15 ml DMF was added nitrile (IV) (1.2 g, 3.9 mmole) and after stirring for 15 minutes at room temperature 1,2-dibromo-ethane (1.1 g, 5.8 mmole) in 1.5 ml DMF was added. The resulting mixture was stirred 0.5 hour at room temperature and then more sodium hydrate (0.114 g, 2.86 mmole) was added and the reaction mixture heated for about 10 minutes at 30-35° C. After cooling the mixture was partitioned between ethylacetate and brine, the organic layer was dried over sodium acetate and concentrated in vacuo. Purification by silica gel column chromatography with 30%-50% ethylacetate in hexane afforded compound (V) 1 g (77% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH:18]=O)[CH2:13]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=CC1CCCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Yield: 69.1 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (18 g, 83.70 mmol), tetrahydro-2H-pyran-3-carbaldehyde (9.55 g, 83.70 mmol) and pyrrolidine (6.95 mL, 83.70 mmol) in MeOH (125 mL) was heated to reflux for 4.5 h. The mixture was allowed to reach r.t. and concentrated. The residue was dissolved in EtOAc (150 mL) and washed with 1M NaOH (80 mL), 1M HCl (80 mL), and brine (80 mL) successively. The organic phase was concentrated, the residue was purified by flash chromatography with a gradient of 10% EtOAc in heptane to 40% EtOAc in heptane to give the title compound (18 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.50 (m, 3 H), 1.79 (m, 0.5 H), 1.94 (m, 1.5 H), 2.67 (m, 1 H), 2.86 (m, 1 H), 3.30 (m, 2 H), 3.78 (m, 1 H), 3.84 (m, 0.5 H), 4.04 (dd, 0.5 H), 4.44 (m, 1 H), 7.05 (dd, 1 H), 7.71 (m, 1 H), 7.79 (d, 1 H); MS (ES+) m/z 311 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].C([N:25]1[C:29]2=NC=[C:32](C(OCC)=O)[C:33](NN)=[C:28]2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:25][C:29]4[N:1]([N:2]=[C:33]([CH3:32])[CH:28]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Product: Cc1cc2[nH]c(=O)c3cnc4c(cnn4Cc4ccco4)c3n2n1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1 a and proceeding as in parts a and b, 8-furfuryl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1, part c, substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 1-furfuryl-2-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])=[O:4].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH3:12])=[O:4]
Reactant: COC(=O)c1scc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1scc(Br)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 129.3 %

Procedure:
Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (−200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:34])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.94 ml of DBU and then 1.54 ml of benzyl bromide are added at RT to a solution of 3 g of 6-(tert-butoxycarbonylamino)hexanoic acid in 60 ml of DCM and the mixture is stirred for 24 hours at RT. It is concentrated under vacuum, the residue is taken up with 100 ml of water and extracted with AcOEt, the organic phase is washed with a 5% solution of potassium carbonate, with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 2.8 g of the expected product, which is used as such.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[CH2:8](OC(OCC)OCC)C.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:21]>C(Cl)(Cl)(Cl)Cl>[NH:4]1[C:3]([NH:2][CH:8]=[N:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]([O:27][CH3:28])=[O:26])=[N:7][N:6]=[N:5]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1nnn[nH]1
Reactant: COC(=O)c1ccccc1N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture was prepared from 12.2 g of 5-aminotetrazole monohydrate, 71.3 g of triethoxymethane, 22.3 g of methyl anthranilate and 100 ml of carbon tetrachloride and this was refluxed under nitrogen with stirring for 16 hours. The mixture was then cooled to room temperature and the white crystals which formed were separated by filtration, washed with carbon tetrachloride and dried to give N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine melting at about 199°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C.ClCCl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:24][CH:21]2[CH2:20][CH2:19][N:18]([CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH2:23][CH2:22]2)[CH:3]=1
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCN(C2CCOCC2)CC1
Yield: 97.6 %

Procedure:
To a mixture of 4-bromo-2-fluoro-1-nitrobenzene (1.05 g, 0.0048 mol) and 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (0.883 g, 0.0048 mol) D9 in dimethylformamide (10 mL) was added diisopropylethylamine (1.175 mL, 0.0068 mol). The resulting mixture was sealed in a 20 mL Biotage Process Vial and irradiated at 200° C. for 1 min in the Smith Synthesizer. After irradiation, dichloromethane (15 mL) was added to the reaction solution. The resulted solution was washed with H2O (2×10 mL). The combined aqueous layers were extracted with dichloromethane (2×10 mL). The organic layers were combined, dried with Na2SO4, and concentrated in vacuo to yield the title compound (1.8 g) which was used in next step directly without purification. MS (ESI): 384 [M+]; 1H NMR (400 MHz, CDCl3): δ 1.68 (6H, m), 2.09 (2H, d), 2.49 (3H, m), 2.89 (2H, d), 3.39 (2H, t), 3.51 (1H, m), 4.04 (2H, dd), 6.72 (1H, dd), 7.01 (1H, d), 8.03 (1H, d), 8.14 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11]1[C:16](=O)C(Cl)=C(Cl)[C:13](=O)[C:12]=1Cl.Cl.C(=O)/C=C/C>CC(O)CC>[CH3:13][C:12]1[CH:11]=[CH:16][C:6]2[C:4](=[CH:3][C:2]([F:1])=[C:8]([F:9])[CH:7]=2)[N:5]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(F)c(F)c1
Agent: C/C=C/C=O
Agent: Cl
Solvent: CCC(C)O
Product: Cc1ccc2cc(F)c(F)cc2n1
Temperature: 50 °C

Procedure:
To a refluxing solution of 3,4-difluoroaniline (2.30 ml, 23.2 mmoles), tetrachloro-1,4-benzoquinone (5.70 g, 23.2 mmoles), and concentrated hydrochloric acid (6 ml) in 2-butanol (40 ml) is added crotonaldehyde (1.92 ml, 23.2 mmoles). After 2.5 hours the reaction mixture is concentrated and the resulting residue is stirred in warm (50° C.) THF (15 ml). This mixture is cooled (0° C.) and the solid collected by filtration and washed with cold THF. The solid is stirred in distilled water (200 ml), and the resulting solution made basic with K2CO3 and extracted with EtOAc (3×100 ml). The organic extracts are combined and dried over sodium sulfate, and then concentrated to give the title compound. MS (ESI) 180 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:24])([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2O)=[C:4]([N+:35]([O-])=O)[CH:3]=1.[N+](C1C=CC=CC=1N=NC1C=C(C(C)(C)C2C=CC=CC=2)C=C(C(C)(C)C2C=CC=CC=2)C=1O)([O-])=[O:39].CC(C1C=C(C(C)(C)C2C=CC=CC=2)C=CC=1O)(C)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][N:9]([C:10]3[CH:11]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[OH:39])[CH:13]=[C:14]([C:16]([CH3:23])([CH3:24])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:35]=[C:4]2[CH:3]=1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Agent: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Product: CC(C)(c1ccccc1)c1cc(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)c2ccccc2O)c1
Yield: 70 %

Procedure:
When, using the general procedure of Example 3, the amount of 4-chloro-2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl)azobenzene was substituted for 2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl )azobenzene, the above-named compound was prepared in a yield of 70.0% as light tan crystalls melting at 160°-161° C. (Compound 2)
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[N:8]([CH3:20])[C:7]1=O)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>C1(C)C=CC=CC=1.O1CCCC1.C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:11]2[CH2:10][CH2:9][N:8]([CH3:20])[CH2:7][C@H:6]2[CH2:4][OH:3])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Reaction time: 3 h

Procedure:
Compound E4 (34 g) in toluene (150 ml) was added slowly to a slurry of lithium aluminium hydride (10 g) in a tetrahydrofuran (50 ml)/toluene (150 ml) mixture, maintaining the temperature at 0°-5° C. under nitrogen. (Commercially available solutions of lithium aluminium hydride in tetrahydrofuran/toluene have also been used successfully). The mixture was stirred for a further 1-5 hours and then allowed to warm up to 15°-25° C. overnight. The excess lithium aluminium hydride was destroyed by the carefully controlled addition of water (10 ml), dilute 15% sodium hydroxide (10 mls) and water (30 ml). The solids were then removed by filtration and reslurried in toluene (100 ml). The combined rich toluene layers were concentrated to a low volume (75 ml) and poured into petroleum ether [100°-120°] (25 ml). After stirring for 8-24 hours the product was isolated by filtration, washed with petroleum ether (10 ml) and dried.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+]>O>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1)=[CH2:10]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc(O)cc1

Procedure:
Into a 2 liter reaction flask equipped with cooling bath, heating mantle, electric stirrer, thermometer and addition funnel is placed 129 grams of paraacetoxy styrene produced according to Example IV(B) and a solution of 112 grams of potassium hydroxide in 1120 ml water. The resulting reaction mass is heated to 35°-40° C. until all the paraacetoxy styrene is consumed by the base. This takes approximately 45 minutes. The reaction mass is then cooled to 20°-25° C. and over a period of 0.5 hours, enough 10% aqueous acetic acid is added to the reaction mass to bring the pH to 6 (630 ml 10% aqueous acetic acid added). At this point, 75 grams of crystals precipitate. The crystals are washed with 150 ml water and air dried to yield food grade, substantially pure paravinyl phenol.