Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH:4]1[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[N:24]=[C:23](N(C)C)[CH:22]=[CH:21][N:20]=1.Cl.[H][H].C[OH:32]>[Pd].CC(O)C>[ClH:1].[ClH:1].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH:4]1[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[NH:24][C:23](=[O:32])[CH2:22][CH2:21][N:20]=1
Reactant: CN(C)c1ccnc(NCCCNCC2CCc3ccccc3O2)n1
Reactant: [H][H]
Reactant: CO
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: O=C1CCN=C(NCCCNCC2CCc3ccccc3O2)N1
Yield: 13.1 %

Procedure:
A mixture of (±)-N2 -[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]N4,N4 -dimethyl-2,4-pyrimidinediamine dihydrochloride (0.0067 mol) in methanol (150 ml) was hydrogenated with palladium on activated carbon 10% (2 g) as a catalyst in the presence of a solution of hydrochloric acid in 2-propanol (2 ml). After uptake of hydrogen (2 eq.), the catalyst was filtered off. The filtrate was evaporated and the residue was crystallized twice from methanol. The crystals were filtered off and dried, yielding 0.32 g (13.1%) of (±)-2-[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]amino]-5,6-dihydro-4(3H)-pyrimidinone dihydrochloride; mp. 273.6° C. (comp. 12-c).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.C=O.[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH3:21][O:22]CCO>O>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([C:7]2[NH:11][C:10]([CH2:15][OH:18])=[C:9]([CH2:21][OH:22])[N:8]=2)=[CH:5][CH:6]=1
Reactant: COCCO
Reactant: Cc1ccc(-c2ncc[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Product: Cc1ccc(-c2nc(CO)c(CO)[nH]2)cc1
Temperature: 95 °C
Yield: 21 %

Procedure:
A mixture of 15.8 g (0.1 mole) of 2-p-tolyl imidazole, 9 g (0.3 mole) of paraformaldehyde, 2 g (0.015 mole) of potassium carbonate, and 50 ml of methyl cellosolve was heated at 95° C. for 30 minutes with stirring in the same way as in Example 1. 200 ml of water was added, and the reaction mixture was boiled for a while and cooled. The crystals were collected by filtration, boiled together with 20 ml of toluene, and cooled. The crystals were collected by filtration and recrystallized from methyl cellosolve to afford 2-p-tolyl-4,5-dihydroxymethyl imidazole as a final product in an amount of 4.5 g (yield 21%). The thin-layer chromatography (cellulose:n-BuOH:AcOH:W = 4:1:2) of the crystals gave only one spot at Rf = 0.73.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].N>ClCCl>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Reactant: CS(=O)(=O)Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCNS(C)(=O)=O)c(Cc3cccc4ccccc34)sc21
Reaction time: 1 h

Procedure:
5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg) and triethylamine (100 μl) were dissolved in dichloromethane (5 ml) and then cooled in ice. Methanesulfonyl chloride (25 μl) was added dropwise and the solution was stirred for 1 h. Aqueous ammonia (dilute) was added and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined, dried, filtered and evaporated. Purification by HPLC (ethyl acetate:isohexane 20-100:80-0) followed by trituration with methanol gave the title compound (43 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:6][C:5]=2[NH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)c[nH]c2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)c[nH]c2C1
Yield: 4.1 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.70 g), aminoguanidine hydrochloride (0.34 g), concentrated hydrochloric acid (0.44 ml), water (0.44 ml) and ethanol (50 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated. To the residue was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/MeOH/Et3N). The resulting oil was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindole hydrochloride (Compound 6) (0.04 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN1CCN(C(Cl)=O)CC1.C(O)C=C.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3
Agent: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C=CCO
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Yield: 85.8 %

Procedure:
40 mg (0.27 mMol) of 5 was reacted overnight with 160 mg (0.81 mMol) of commercially available 4-methylpiperazine carbonylchloride hydrochloride in 17 mL of DCM with 1.7 mL of allylalcohol and 214 μL pyridine. The aolvent was evaporated and the crude compound was purified over silica with 5% MeOH/DCM as eluent to give 70 mg (40% yield) of 6. M+1=645.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH3:22][Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][Si:23]([CH3:33])([CH3:32])[CH3:22])=[CH:31][CH:30]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: C[Si](C)(C)Oc1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(O[Si](C)(C)C)cc1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
Monoimine (1, 1.4 g, 5 mmol) and 4-trimethylsiloxyaniline (8, 906 mg, 5 mmol) were dissolved in 50 ml of toluene. To this solution 4 Å molecular sieves were added. After standing at room temperature for 4 days with addition of more molecular sieves the reaction mixture was filtered and the solvent was removed in vacuo. The product was washed with a small amount of methanol. Yield 1.4 g (63%) of mixed diimine (9). 1H NMR (CDCl3) δ 8.42 (dd, 1H), 8.33 (dd, 1H), 7.86 (t, 1H), 6.88 (s, 2H), 6.86 (d, 2H), 6.74 (d, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.00 (s, 6H), 0.27 (s, 9H).
Reaction SMILES: [Li+].[C:2]([CH2:4][CH2:5][CH:6]([P:11]([O:16]CC)([O:13]CC)=[O:12])[S:7]([O-:10])(=[O:9])=[O:8])#[N:3].[H][H]>N.[Rh]>[NH2:3][CH2:2][CH2:4][CH2:5][CH:6]([P:11]([OH:16])([OH:13])=[O:12])[S:7]([OH:10])(=[O:8])=[O:9]
Reactant: CCOP(=O)(OCC)C(CCC#N)S(=O)(=O)[O-]
Reactant: [H][H]
Agent: [Rh]
Agent: N
Agent: [Li+]
Product: NCCCC(P(=O)(O)O)S(=O)(=O)O

Procedure:
The hydrogenation of 3-cyano-1-diethoxyphosphinylpropanesulfonic acid lithium salt is carried out using the hydrogenation technique of Freifelder (J. Am. Chem. Soc., 82, 2386 (1960)). The cyano compound (2.62 g; 0.01 mole) is placed in 20 ml of 10% methanolic ammonia. Rhodium on alumina (5%) catalyst (0.5 g) is added, and the mixture is hydrogenated at 40 PSI on a Parr apparatus for several hours (until uptake of hydrogen is complete). The catalyst is filtered off, and the filtrate is evaporated dry. The product is hydrolyzed by dissolving the residue in 25 ml of 6N HCl and refluxing the solution for 12-24 hours. It is then evaporated to dryness under vacuum on a rotary evaporator. Distilled water (25 ml) is added, and the solution is again evaporated dry. The resulting residue is dissolved in a few ml H2O, and ethanol is added to precipitate a solid. This is recrystallized from water/ethanol to yield 4-amino-1-phosphonobutanesulfonic acid.
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@H:6](O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)[F:36])(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@@H:6]([F:36])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](O)C(=O)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](F)C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(S)-hydroxypropionate G-3 (5 mmol) in DCM (5 mL) was added pyridine (15 mmol), the reaction was cooled to −20° C., then triflic anhydride was added (7.5 mmol). The solution was stirred for 1 hour, then washed with aqueous citric acid, sodium bicarbonate and brine, then dried (Na2SO4) and concentrated. The intermediate triflate was then resuspended in DCM and cooled to −50° C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (5 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated then purified on silica gel (ethylacetate/hexanes) to afford 2.3 mmol (45%) of methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(R)-fluoropropionate G-4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[F:15].[OH-].[K+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:15]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(Cl)c(F)c1
Yield: 95.6 %

Procedure:
A solution of methyl 2-(4-chloro-3-fluorophenyl)-2-methylpropanoate (2.94 g, 12.7 mmol) and KOH (7.15 g, 127 mmol) in EtOH (90 mL) and water (30 mL) was stirred at 150° C. in a sealed vessel for 3 hours. The solution was concentrated in vacuo, diluted with 10% HCl (aq) (150 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (2×100 mL) and then with brine (75 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give 2-(4-chloro-3-fluorophenyl)-2-methylpropanoic acid (2.63 g). MS m/e=217.3 (M+H)+.
Reaction SMILES: [OH-].[K+].Cl.[NH2:4]O.[CH2:6]([S:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].BrCCBr>CO>[CH2:6]([S:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]1[O:18][CH2:19][CH2:24][O:27][N:4]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: NO
Reactant: COC(=O)c1ccccc1SCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: BrCCBr
Product: c1ccc(CSc2ccccc2C2=NOCCO2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
160 g (2.86 mol) of potassium hydroxide in 700 ml of methanol are added dropwise, at room temperature, to a mixture of 98.7 g (1.42 mol) of hydroxylamine hydrochloride and 700 ml of methanol. Subsequently, 184 g (0.712 mol) of methyl 2-(benzylthio)benzoate are added in portions at room temperature. The mixture is stirred at 40° C. overnight. 98.1 g (0.712 mol) of potassium carbonate are then added, 601 g (3.20 mol) of 1,2-dibromoethane are added dropwise, and the mixture is left stirring at 60° C. overnight. Subsequently, the solvent is distilled off under reduced pressure. The residue is partitioned between methylene chloride and water. The organic phase is dried and the solvent is distilled off under reduced pressure. The residue is stirred up with absolute ethyl alcohol. The solid is filtered off with suction and dried under high vacuum. 43.1 g (21% of theory) of 1-benzylthio-2-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)benzene are obtained as a pale yellow solid. Melting point: 73°-77° C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20]>>[CH3:20][C:19]1[N:21]=[CH:4][C:5]2[CH2:6][C:7](=[O:17])[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:22]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Agent: Cl
Product: Cc1ncc2c(n1)-c1ccccc1NC(=O)C2
Yield: 44 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and acetamidine hydrochloride. Yield: 44%.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][C:6]([NH:8][CH2:9][C@@H:10]([NH:18]C(=O)OC(C)(C)C)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7].C(OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>CCO.CCO.O>[NH2:18][C@@H:10]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:9][NH:8][C:6](=[O:7])[O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:27])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOC(=O)NC[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
(S)-tert-butyl 1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (8.5 g, 0.0213 mol) was dissolved into a minimal volume of ethyl ether (120 mL) and added to a solution of tosic acid (4.46 g, 0.023 mol) in 25 mL of absolute EtOH. This solution was placed on a rotary evaporator and ethyl ether was removed at ambient temp. The flask was then lowered into the water bath (temperature: 60° C.) and the selective de-protection of the Boc group proceeded concurrently with removal of the remainder of solvent. The reaction was completed by 2 h and gave an off-white solid. This material was cooled to rt and dissolved in 100 mL of a mixture EtOH:H2O (1:1, v/v). This was washed with hexanes:EtOAc (5:1, v/v, 3×12 mL), basified with 1N NaOH (pH>10), and extracted with EtOAc (3×50 mL). The combined organic extracts were washed (3×5 mL 1N NaOH, 3×5 mL brine), dried, decanted and stripped to give the free base of (S)-2-(trimethylsilyl)ethyl 2-amino-3-cyclohexylpropylcarbamate (5.24 g, 82%). 1H NMR (400 MHz, CDCl3): 5.09 (brs, 1H), 4.14 (t, J=8.4 Hz, 2H), 3.23 (m, 1H), 2.88 (m, 2H), 1.75-1.48 (m, 5H), 1.5-0.75 (m, 10H), 0.05 (s, 9H). MS (E/Z): 301 (M+H+).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[O:43]1[C:47]2([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[O:46][CH2:45][CH2:44]1>C(#N)C>[O:43]1[C:47]2([CH2:52][CH2:51][N:50]([C:1](=[O:2])[CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:49][CH2:48]2)[O:46][CH2:45][CH2:44]1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)N1CCC2(CC1)OCCO2
Yield: 83.5 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (254 mg, 0.67 mmol, 1.0 eq), N-methylmorpholine (96 uL, 0.88 mmol, 1.30 eq) in acetonitrile (7 mL) was treated with isobutyl chloroformate (96 uL, 0.74 mmol, 1.1 eq) followed by 1,4-dioxa-8-aza-spiro[4.5] decane (0.193 g, 1.35 mmol, 2.0 eq). Purification by flash chromatography provided 280 mg (83%) of L-isoleucine, N-[1-(2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxoethyl)-L-Prolyl] benzylamide as a colorless oil
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].C(N(CC)CC)C.[Cl:19][C:20]1[N:29]=[C:28](Cl)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1>CC(O)C>[Cl:19][C:20]1[N:29]=[C:28]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: N#Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(CNc2nc(Cl)nc3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Yield: 86.7 %

Procedure:
3.9 g of 3-chloro-4-methoxybenzylamine, 3.97 g of triethylamine and 200 ml of 2-propanol were added to 4 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes, cooled to room temperature and filtered to recover a crystalline precipitate. The precipitate was washed with water and chloroform successively to give 5.563 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:14](OC)(OC)[O:15]C.[CH3:21]O>[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:21][O:13][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([O:15][CH3:14])[CH3:12]
Reactant: CO
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: COC(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: COC(C)(OC)c1ccc(C(C)(C)C)cc1

Procedure:
To a stirred solution of 4′-tert-butylacetophenone (purcashed from Aldrich, 1.76 g, 10 mmol) in MeOH (1 mL) was added trimethyl orthoformate (1.97 g, 11 mmol) and tetrabutylammonium tribromide (48.2 mg, 0.1 mmol) successively. The same reaction procedure as described in Example 63A was performed to give the title compound (2.33 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11]CC)=O)=O)=[CH:4][CH:3]=1.[Cl:16][C:17]1C=CC(C(=O)C)=CC=1.C(=O)(OCC)OCC.[H-].[Na+].[C:36]1([NH:42][NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.ClC1C=CC(C2CC(=O)N(C3C=CC=CC=3)N=2)=CC=1>C(O)C.C(O)(=O)C>[Cl:16][C:17]1[N:42]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:43]=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)[C:8]=1[CH:9]=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: O=C1CC(c2ccc(Cl)cc2)=NN1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: O=Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl

Procedure:
50.8 g of ethyl p-chlorobenzoylacetate (produced for example from p-chloroacetophenone, diethyl carbonate and sodium hydride with a yield of 72%), 24 g of phenylhydrazine, 5 ml of glacial acetic acid and 150 ml of ethanol are heated in a nitrogen atmosphere for 1 hour at boiling point. After cooling in an ice bath 3-p-chlorophenyl-1-phenyl-2-pyrazoline-5-one is obtained with a yield of 84 %; F 160.5°-161.5°.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Li+]>COCCOC.O>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[C:3]([OH:25])=[O:2])=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
N-(3,3-diphenylpropionyl)-L-proline methylester (2.10 g, 6.23 mmol) was dissolved in DME (50 ml) and H2O (50 ml). Lithium hydroxide monohydrate (1.57 g, 37.39 mmol) was added and the mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated to remove DME and the remaining aqueous layer was acidified with 1N HCl to pH 3. The acidic layer was washed with EtOAc (3×75 ml). Organic washes were combined, dried with Na2SO4, filtered and concentrated to give 1.92 g (94%) of N-(3,3-diphenylpropionyl)-L-proline.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][C:17](=O)[CH3:18])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].BrCC[CH2:29][CH2:30][CH2:31][CH2:32][Cl:33]>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][CH2:17][CH2:18][CH2:29][CH2:30][CH2:31][CH2:32][Cl:33])([CH3:3])[CH3:2]
Reactant: ClCCCCCCBr
Reactant: CC(=O)SCC(=O)Nc1c(C(C)C)cccc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CSCCCCCCCl
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a mixture of 29.3 g of N-(2,6-diisopropylphenyl)-2-(acetylthio)acetamide and 240 ml of ethanol was added dropwise 27 ml of a 30% aqueous sodium hydroxide solution at 0° C. in an argon atmosphere. After stirring for 30 minutes, 20.0 g of 1-bromo-6-chlorohexane was added thereto, followed by stirring at room temperature for 4 hours. To the reaction mixture was added 50 ml of water to yield 36.0 g of N-(2,6-diisopropylphenyl)-2-(6-chlorohexylthio)acetamide as colorless needle crystals having a melting point (m.p.) of 86.5° to 87.5° C.
Reaction SMILES: [CH2:1]1[CH:6]2[CH:7]3[CH:13]4[CH2:14][CH:2]1[CH2:3][CH:4]1[CH:12]4[CH2:11][CH:9]([CH2:10][CH:5]12)[CH2:8]3.C(Cl)Cl.[N+]([O-])(O)=[O:19].OS(O)(=O)=O.[OH2:27]>CO>[CH2:14]1[C:2]2([OH:27])[CH2:1][CH:6]3[CH:5]4[CH2:10][C:9]5([OH:19])[CH2:11][CH:12]([CH:4]4[CH2:3]2)[CH:13]1[CH:7]3[CH2:8]5
Reactant: O=[N+]([O-])O
Reactant: O
Reactant: C1C2CC3C4CC5CC(C14)C(C2)C3C5
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: OC12CC3C4CC5(O)CC3C(C1)C(C5)C4C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Diamantane 1 (1.28 g, 0.149 mol), CH2Cl2 (250 mL) and 100% HNO3 (90 mL, 2.13 mol) are mixed at 0° C., stirred for 2 h at 25° C. and subsequently diluted with water (180 mL). The CH2Cl2 is removed and the reaction mixture 26 is refluxed for 1.5 h. Removal of the water in the vacuum yielded a mixture of different oligohydroxydes 20 as a remainder. These 20 are added to 200 mL of 96% H2SO4 and stirred for 2 h at room temperature. Subsequently, the reaction mixture is poured onto 300 g ice and filtered. Extraction of the filtrate with one or several organic solvents (typically diethylether) yields 21.3 g (0.097 mmol, 65%) 4.9-dihydroxydiamantane (2, m=0) as white solid, mp. 291-293° C. (from methanol, literature 290-292° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:41])=[C:38]([OH:40])[CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:17]=2[O:40][C:38]2[CH:39]=[C:34]([F:33])[CH:35]=[CH:36][C:37]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccc(F)cc3)c3ccncc23)CC1
Reactant: Cc1ccc(F)cc1O
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cnccc2n1-c1ccc(F)cc1

Procedure:
The crude title compound was prepared from the compound of step 5 (50.0 mg, 109 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6.