Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])/[C:4]/1=[CH:14]/[C:15]([NH:17]C(=O)C1C=CC=CC=1)=S>CO>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH:4]1[CH2:14][C:15]#[N:17]
Reactant: CN1/C(=C\C(=S)NC(=O)c2ccccc2)C(C)(C)c2ccccc21
Agent: [Na]
Solvent: CO
Product: CN1c2ccccc2C(C)(C)C1CC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500-mL one-necked flask was equipped with a magnetic stir bar and a reflux condenser. 200 mL of methanol were added to the flask, sodium (3.0 g, 0.13 mole) was added to the methanol as small pieces (approximately 0.5 g). After the sodium dissolved, N-[(2Z)-2-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)ethanethioyl]-benzamide (19.0 g, 0.056 mole) was added to the flask and the reaction mixture was heated at reflux with stirring for 2 hours. The reaction mixture was cooled to room temperature and the methanol was evaporated using a rotary evaporator. The residue was treated with 200 mL of water and extracted with dichloromethane (3×100 mL). Combined organic extracts were dried over magnesium sulfate and the solvent was evaporated on a rotary evaporator. The red solid was recrystallized from methanol-water (7:3) to give slightly red crystals. The yield was 4.5 g (40% of theory). Mp=74-76° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:7][C:8](=[O:15])[C@@H:9]([NH2:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1.C(OC(Cl)=O)C(C)C.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:7][C:8](=[O:15])[C@@H:9]([NH:14][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[O:25])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH3:6])[CH3:2]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)C1CCN(C)CC1)C(C)(C)C

Procedure:
For compound (A48) (S)-2-((S)-2-Amino-3,3-dimethyl-butyrylamino)-propionic acid ethyl ester was coupled with 1-Methyl-piperidine-4-carboxylic acid using isobutylchloroformate and N-methylmorpholine in DMF to give (S)-2-{(S)-3,3-Dimethyl-2-[(1-methyl-piperidine-4-carbonyl)-amino]-butyrylamino}-propionic acid ethyl ester. This was then quaternised with MeI in DCM-acetone and subsequently hydrolysed using an hydroxide resin such as Ambersep 900-OH resin.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(=O)CC>[CH3:24][C:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1
Yield: 46 %

Procedure:
A mixture of 139.1 g. (1 mol) 4-nitrophenol, 1 liter butan-2-one and 207.3 (1.5 mol) pulverized, anhydrous potassium carbonate is stirred for 2 hours at reflux temperature, then 292.5 g. (1.5 mol) ethyl 2-bromo-2-methylpropionate are added thereto and the reaction mixture maintained at reflux temperature for a further 92 hours. After the addition of a further 69.1 g. (0.5 mol) potassium carbonate and 97.5 g. (0.5 mol) ethyl 2-bromo-2-methyl-propionate, the reaction mixture is stirred for a further 20 hours at reflux temperature. The reaction mixture is then filtered with suction and the filtrate is evaporated in a vacuum (for the removal of excess ethyl ester, finally at a high vacuum). The residue is taken up in diethyl ether, filtered and the ethereal phase now extracted several times with 1 N aqueous sodium hydroxide solution. After washing until neutral and drying, it is evaporated, 153 g. (60% of theory) of an oily crude product being obtained. After distillation at 155.5°-156° C./0.05 mm.Hg., there is obtained a yield of 46% of theory of pure ethyl 2-methyl-2-(4-nitrophenoxy)-propionate in the form of a yellow oil with a refractive index of nD20 =1.5288.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1>N1C=CC=CC=1>[OH:14][C:11]1[CH:12]=[CH:13][C:4]([C:3]([O:2][CH3:1])=[O:15])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(O)c(C(=O)O)c1
Yield: 99.6 %

Procedure:
A solution of dimethyl-4-hydroxyisophthalate (10.0 g, 47.6 mmol) in pyridine (70 mL) was heated to reflux for 15 h. The reaction mixture was concentrated in vacuo and acidified with 1N HCl at 0° C. The resulting solid was collected by filtration, washed with water and dried in vacuo to provide the title compound (9.3 g, 100%) as a white solid. 1H NMR (DMSO-d6) δ 8.40 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.4, 2.0 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 3.84 (s, 3H); MS(ESI−) m/z 195.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 498.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[C:23]1([C@@H:29]2[CH2:31][C@H:30]2B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][S:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[CH:3][C:2]([C@@H:30]1[CH2:31][C@H:29]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:11][CH:10]=2)(=[O:15])=[O:14]
Reactant: OB(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc2ccc(Br)cc2c(N2CCOCC2)c1S(C)(=O)=O
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccc([C@@H]3C[C@H]3c3ccccc3)cc2c(N2CCOCC2)c1S(C)(=O)=O
Yield: 61.3 %

Procedure:
6-Bromo-3-methanesulfonyl-2-methyl-4-morpholin-4-yl-quinoline (compound of example 6) (300 mg, 0.78 mmol), trans-2-phenylcyclopropylboronic acid (189 mg, 1.17 mmol), potassium phosphate (496 mg, 2.33 mmol) and tetrakis(triphenylphosphine)-palladium (27 mg, 0.023 mmol) were heated at reflux under argon for 8 h. The crude product was purified by chromatography on silica gel in dichloromethane/ethyl acetate 5:1 with a gradient from 100:0 to 80:20. One obtained 202 mg (60%) of white crystals. MS: m/z=423 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([S:12][CH2:13][CH3:14])=[N:7][N:6]=[CH:5]2.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([S:12][CH2:13][CH3:14])=[N:7][N:6]=[CH:5]4)[CH:21]=2)[CH2:16][CH2:17]1
Reactant: CCSc1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: CCSc1nncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc12
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-1-(ethylthio)phthalazine (1.87 g), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.3 g, 0.9 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.05 g, 0.05 mmol) in DME/EtOH (4:1) (5 mL) was treated with the 2 M aqueous solution of potassium carbonate (1 mL, 3 mmol). The mixture was heated at 90° C. for 1 h. The mixture was cooled, diluted with ethyl acetate (100 mL), washed with water (3×20 mL), brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography eluting with 1-5% 2 M ammonia methanol/dichloromethane to give the title compound as pale yellow solid. Found MS(ES+): 364(M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:17]([C:22]([CH3:26])([CH3:25])[C:23]#N)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1.C(OCC)(=[O:29])C.[OH-].[Na+]>O.S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([N:15]2[C:16]3=[N:21][CH:20]=[CH:19][N:18]=[C:17]3[C:22]([CH3:26])([CH3:25])[C:23]2=[O:29])[CH2:14]1
Reactant: CC(C)(C#N)c1nccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2nccnc21
Temperature: 100 °C
Reaction time: 0.58 h

Procedure:
2-(3-((Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)amino)pyrazin-2-yl)-2-methylpropanenitrile (0.067 g, 0.184 mmol) was dissolved in a mixture of water (3 mL) and concentrated sulfuric acid (2 mL) and heated at 100° C. After 35 minutes the heat was turned off and the reaction allowed to cool in the oil bath over 90 minutes. Water (100 mL), ice (about 100 mL), and ethyl acetate (200 mL) were added followed by 5 N sodium hydroxide (15 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 5-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.061 g, 0.167 mmol, 91% yield) as a white solid. M+1: 366.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 6 H) 2.42-2.58 (m, 2 H) 3.45 (s, 2 H) 4.53-4.68 (m, 1 H) 5.31 (quin, J=8.46 Hz, 1 H) 6.53 (br. s, 1 H) 7.04-7.15 (m, 1 H) 7.30 (t, J=7.24 Hz, 1 H) 7.59 (d, J=8.22 Hz, 1 H) 7.61 (d, J=8.02 Hz, 1 H) 8.09 (d, J=3.33 Hz, 1 H) 8.13 (d, J=3.30 Hz, 1 H).
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O-:12])=O.[NH:23]1[C:31]2[C:26](=CC=CC=2)[CH2:25][CH:24]1[C:32](O)=[O:33].[OH-].[Na+].C(Cl)(OCC1C=CC=CC=1)=O>O>[C:17]1([CH2:16][O:15][C:13]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH:2]2[C:10]([N:23]2[CH2:31][CH2:26][CH2:25][CH:24]2[CH2:32][OH:33])=[O:12])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(C1Cc2ccccc2N1C(=O)OCc1ccccc1)N1CCCC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
2,3-dihydro-1H-indole-1,2-dicarboxylic acid, 1-(phenylmethyl) ester. 10.0 g (0.0612 mol) of indoline-2-carboxylic acid was added to 100 ml of water and 1N NaOH was added to the solution until the pH was 8.0. To the resulting solution, 9.10 ml (0.0637 mol) carbobenzyloxychloride was added dropwise. The reaction mixture was stirred for 1 hour at room temperature while keeping the pH between 7.5 and 8.5 with addition of 1N NaOH. The mixture was then extracted with ether and the ether extracts discarded. The pH of the reaction mixture was then adjusted to 6.3 and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried, and evaporated. The residue was chromatographed on silica gel eluting with 3:7/ethyl acetate:hexane. Fractions containing the desired material were combined and evaporated to yield 9.3 g (51%) of the title compound as a white amorphous solid. TLC (10:1/chloroform:methanol) Rf =0.25. 1H NMR (CDCl3) δ: 6.8-7.9(m,9H); 4.8-5.4(m,3H); 3.50(m,1H); 3.20(m,1H).
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][O:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.[CH3:21][Si:22]([CH3:25])([CH3:24])Cl>CCCCCC>[CH3:10][C:2]([O:1][Si:22]([CH3:25])([CH3:24])[CH3:21])([CH2:6][CH2:7][O:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)CCOC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCC(C)(CCOC)O[Si](C)(C)C

Procedure:
To a solution of 13 g. (0.091 moles) of 4-hydroxy-4-methyl-7-oxa-1-octyne and 16 g. (0.235 moles) of imidazole in 80 ml. of dry dimethylformamide is added dropwise, at 5° C. under nitrogen with stirring, 12.5 ml. (0.115 moles) of trimethylchlorosilane. After an additional 15 minutes at 5° C. the solution is stirred at ambient temperature for 18 hours then added to 450 ml. of hexane. The resulting solution is washed with ice-cold water, ice-cold saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness in vacuo. Distillation of the residual oil furnishes 16.8 g. (86%) of product; b.p. 87°-88° C. (7 mm.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N:7]1([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:21][CH:20]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+].O>O1CCCC1>[OH2:3].[CH2:5]([O:4][C:2]([N:10]1[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)=[O:3])[CH3:6].[CH2:5]([O:4][C:2]([N:10]1[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: O=C(COc1ccc(C2=NNC(=O)NC2)cc1)NCCN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(CCNC(=O)COc2ccc(C3=NNC(=O)NC3)cc2)CC1
Reaction time: 0.5 h

Procedure:
0.15 ml of ethyl chloroformate were added, whilst ice-cooling, to a mixture of 0.360 g of N-[2-(1-piperazinyl)ethyl]-α-[4-(2,3,4,5-tetrahydro-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetamide [prepared as described in step (a) above], 0.13 g of sodium bicarbonate, 10 ml of water and 50 ml of tetrahydrofuran, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluent: a 1:1 by volume mixture of ethanol and methylene chloride), followed by recrystallization from ethanol, to give 0.264 g of the title compound as colorless fine crystals melting at 200°-240° C. (with decomposition).
Reaction SMILES: C(C1C=CC=CC=1C(C)C)(C)C.C(C1C=CC=CC=1C(C)C)(C)C.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[CH:29]=1)([CH3:27])[CH3:26].[O:37]=[O:38].[OH:39][O:40]O.C(C1C=CC=C(C(C)C)C=1)(C)C>>[O-:39][OH:40].[O-:37][OH:38].[CH:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=1)([CH3:36])[CH3:35]
Reactant: OOO
Reactant: O=O
Agent: CC(C)c1cccc(C(C)C)c1
Agent: CC(C)c1ccccc1C(C)C
Product: [O-]O

Procedure:
The objects of the present invention are achieved by a process in which diisopropylbenzene, comprised of m-diisopropylbenzene diisopropylbenzene and less than 6% o-diisopropylbenzene, is oxidized under anhydrous, non-alkaline conditions with oxygen or air at about 85° C.-95° C. in a continuous process. The hydroperoxidation method of the present invention produced a 92.8% yield of m-diisopropylbenzene dihydroperoxide (m-DHP) and m-diisopropylbenzene hydroxyhydroperoxide (m-HHP), of which approximately 75% was m-DHP and 25% was m-HHP. Furthermore, the composition remains substantially the same through at least ten cycles of batch operations.
Reaction SMILES: O=[C:2]([C:21]1[NH:25][N:24]=[N:23][N:22]=1)[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Cl:14])[C:12]=1[Cl:13])[CH2:9][C:8]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:15])[CH2:7]2.Cl.[NH2:27][OH:28].Cl>N1C=CC=CC=1>[N:27](=[C:2]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Cl:14])[C:12]=1[Cl:13])[CH2:9][C:8]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)([CH3:15])[CH2:7]2)[C:21]1[NH:22][N:23]=[N:24][N:25]=1)[OH:28]
Reactant: CC1(C2CCCC2)Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C2CCCC2)Cc2cc(OC(=NO)c3nnn[nH]3)c(Cl)c(Cl)c2C1

Procedure:
A stirred solution of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxymethyl)tetrazole (5.7 g., 0.015 mole) and hydroxylamine hydrochloride (3.2 g., 0.045 mole) in pyridine (60 ml.) is heated at 95°C. on a steam bath for 30 hours then poured into aqueous hydrochloric acid affording 5-(1-hydroximino-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxymethyl)tetrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22]OC(OC)OC>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:22]=[N:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Solvent: O=CO
Product: Clc1cccc(C(c2ccc3[nH]cnc3c2)n2ccnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
A mixture of 2.99 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 50 parts of trimethoxymethane and 2.4 parts of formic acid was stirred for 16 hours at room temperature. The reaction mixture was evaporated. The residue was dissolved in hydrochloric acid solution 2N. This solution was treated with ammonia and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 1.8 parts (58.2%) of 5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole; mp. 108.2° C. (compound 93).
Reaction SMILES: [N+](C1C=CC(C([O:10][CH:11]2[CH2:16][CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])([CH3:17])[CH2:13][CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:10][CH:11]1[CH2:12][CH2:13][C:14]([CH3:17])([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16]1
Reactant: COC(=O)C1(C)CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(C)CCC(O)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Into a 250-mL round-bottom flask containing a solution of 4-(methoxycarbonyl)-4-methylcyclohexyl 4-nitrobenzoate (4.5 g, 14.00 mmol, 1.00 equiv) in methanol/water (30 mL/6 mL) was added potassium carbonate (5.8 g, 41.97 mmol, 3.00 equiv) and the resulting solution was stirred overnight at 50° C. The reaction was quenched by the addition of NH4Cl (aq.) and extracted with 3×100 mL of ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2) to afford the desired methyl 4-hydroxy-1-methylcyclohexane-1-carboxylate (2.2 g, 91%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:21][C:22]([CH3:24])([Si:25]([CH3:27])([CH3:26])[O:15][CH2:14][C@H:9]([C:10]([O:12][CH3:13])=[O:11])[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:23]
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of (R)-methyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture stirred for 4 h. The solvents were removed in vacuo and dissolved in EtOAc (300 mL). The solution was washed with saturated NH4Cl (2×100 mL), then with saturated NaHCO3 (100 mL), and brine (100 mL). The organic layer was then dried, filtered, and solvent removed in vacuo to give (R)-methyl 2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecane-6-carboxylate (40 g, yield 95%) as an oil that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.34 (brs, 1H), 4.35 (m, 1H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 3.82 (dd, J=14, 4.4 Hz, 1H), 1.45 (s, 9H), 3.73 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[N:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:51][CH2:50][C@:41]3([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:42][CH2:43][N:39]([C:37]([C:27]4[CH:28]=[C:29]([N:32]5[CH:36]=[N:35][N:34]=[N:33]5)[CH:30]=[CH:31][C:26]=4[O:25][CH3:24])=[O:38])[CH2:40]3)[CH2:19][CH2:18]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCOCC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CCOCC3CC3)CC2)(c2ccccc2)C1
Temperature: 81 °C
Yield: 70.3 %

Procedure:
Heat at 81° C. a mixture of 1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole (0.10 g, 0.33 mmol) and methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.60 g, 1.27 mmol, example 47.2), triethylamine (0.136 mL, 3 equivalents), sodium iodide (0.097 g, 2 equivalents) and acetonitrile (8.1 mL) under argon for 30 hours. Quench the reaction as described in Example 113. Purify the crude material by column chromatography (silica gel, 4.5 cm×15 cm, using step gradient elution with 0%, 5% and 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.16 g of the title compound, Rf=0.33 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt, m.p. 135-155° C. (dec.), by methods well known in the art.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](Cl)(Cl)=[S:15].O>O1CCOCC1>[N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=[C:14]=[S:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1ccccc1N1CCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 2-piperidinoaniline (17.6 g) in dioxane (100 ml) was added over 25 minutes to a mixture of thiophosgene (10.2 ml) and water (200 ml) which had been cooled to 0° C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice (200 g) and water (200 ml) were added and the mixture extracted with ether (6×50 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried and evaporated to give a residue which purified by chromatography on a silica column eluted with hexane to give 2 -piperidinophenyl isothiocyanate as an oil.