Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([OH:22])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[C:5]([Br:3])(=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Br)Br
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)Br
Temperature: 50 °C

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 7.75 ml (100 mmol) of thionyl bromide, and a water condenser, is placed 12.82 g (50 mmol) of palmitic acid. Addition of the thionyl bromide is completed with heating to about 50° C. over the course of about 50 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, palmitoyl bromide. This acyl bromide, 16.02 g (50 mmol), is put into a dry separatory funnel and combined with 75 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15].[OH-].[Na+]>>[CH3:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[NH:8][C:14](=[O:15])[C:13](=[O:17])[NH:1]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 518.2 %

Procedure:
To a stirred solution of 3,4-diaminotoluene (0.302 g, 0.247 mmol, Aldrich) in 2 N HCl (4 mL, 8 mmol), oxalic acid dihydrate (0.330 g, 0.261 mmol, Fisher) was added in one portion. The resulting deep purple solution was refluxed for 13 h, to give a purple suspension. This was cooled to 25° C., filtered, washed with water (5 mL), and dried in vacuo (0.1 mm Hg) to give a blue-grey powder. This was taken up in 2 N NaOH (34 mL, 68 mmol), giving a brown solution, which was filtered. The brown filtrate was acidified to pH 1.0 by addition of 2 N HCl (42 mL, 84 mmol), resulting in a tan suspension. Filtration of the suspension and washing of the filter cake with water (5 mL) gave the title compound as a grey powder (225.5 mg, 43%); mp 318° C. (the block was preheated to 300° C.); 1H NMR (DMSO-d6) δ 2.32 (s, 3H), 6.90-6.99 (m, 3H), 11.22 (s, 1H), 11.90 (s, 1H).
Reaction SMILES: [Br-].[CH2:2]([P+:13](C1C=CC=CC=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-:32].[Na+]>CO>[C:14]1([P:13](=[O:32])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCP(=O)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
A stirred mixture of undecyl-triphenyl-phosphonium bromide (45.7 g), methanol (300 ml) and 2M sodium hydroxide solution (300 ml) was heated at 50° C. for 3 hours and then concentrated under vacuum until the oily product solidified. The solid was washed with water, dried and recrystallised from petroleum spirit to give diphenyl-undecylphosphine oxide, m.p. 69° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1)=[O:1]
Reactant: COc1cc(C(C)C)ccc(CO)c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)C)ccc(C=O)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (20 g, 96 mmol) was dissolved in chloroform (300 ml), to which was added active manganese dioxide (80 g, 920 mmol) in several portions, and the resultant was stirred at room temperature for 4 hours. The insoluble matter was removed by filtration under reduced pressure, the filtrate was concentrated under reduced pressure and the resulting crude product was recrystallized from toluene to give 12.31 g of 7-formyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as yellow needle-like crystal (yield: 62%). Melting point of the product was 73°-75° C. 10% aqueous sodium hydroxide (50 ml) was added to the aldehyde (5 g, 24 mmol) and stirred overnight at room temperature. The reaction solution was acidified with 10% dilute hydrochloric acid, then extracted with methylene chloride, washed with water, dried, and solvent was distilled off to give a crude crystal (4.78 g). The crude crystal was recrystallized from ethyl acetate/hexane to give 7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a colorless needle-like crystal (yield: quantitative). This compound showed melting point of 76° C., which is identical to that described in the literature (Sci. Repts. Tohoku Univ., I, 37, 367 (1953)]. The compound (1.94 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml), to which was added dropwise 2M phenyl lithium solution (5.2 ml, ca 10 mmol) in a nitrogen atmosphere while cooling to -78° C. The resultant was stirred for 10 minutes. An aqueous saturated sodium chloride was added to the reaction solution, and the resultant was extracted with methylene chloride, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography to give 1.95 g of 7-(α-hydroxybenzyl)-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as brown oil (yield: 71%). The compound (1 g, 3.7 mmol) and 1-(4-chlorobenzhydryl)piperazine (1.27 g, 4.4 mmol) were heated and refluxed in xylene (20 ml) for 2 hours, solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [(ethyl acetate/hexane (1:2)] to give 1.71 g of 7-{1-[4-(4-chlorobenzhydryl)piperazinomethyl]-α-phenyl}-4-isopropyl-2-hydroxyl-2,4,6-cycloheptatrien-1-one (yield: 86%).
Reaction SMILES: [Cl:1]Cl.[C:3]([NH:7][N:8]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>CCCCC>[C:3]([N:7]=[N:8][C:9]([Cl:1])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(=NNC(C)(C)C)c1ccccc1
Reactant: ClCl
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N=NC(C)(Cl)c1ccccc1

Procedure:
1-t-Butylazo-1-chloro-1-phenylethane was prepared in 99% crude yield by adding 34.8 grams (0.49 moles) of chlorine to a pentane solution of 92.8 grams (0.49 moles) of acetophenone t-butylhydrazone and 50.5 grams (0.50 moles) of triethylamine at 0° C., filtering off the insoluble triethylamine hydrochloride that forms and evaporating the pentane under reduced pressure. The yield was 109 grams of a yellow liquid.
Reaction SMILES: [Cl:1][C@H:2]1[C@@H:10]2[C@@H:6]([CH2:7][N:8](C(Cl)=O)[CH2:9]2)[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.Cl>O1CCCC1>[ClH:1].[Cl:1][C@H:2]1[C@@H:10]2[C@@H:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)N1C[C@@H]2[C@H](Cl)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: Cl
Solvent: C1CCOC1
Product: Cl[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Yield: 188.1 %

Procedure:
A solution of 0.4 g of (3aR,7R,7aR)-7-chloro-2-chlorocarbonyl-4,4-diphenylperhydroisoindole in 6 cm3 of a 1N aqueous solution of hydrochloric acid and 14 cm3 of tetrahydrofuran is heated at 80° C. for 9 hours, with stirring. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). 0.35 g of (3aR,7R,7aR)-7-chloro-4,4-diphenylperhydroisoindole hydrochloride is obtained in the form of a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)c1ccccc1OCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCOc3ccccc3C(=O)OC)c2n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound obtained in Example 2-1 step (v) was dissolved in dimethylformamide (50 ml), and potassium carbonate (3.52 g) and methyl 2-(2-bromoethoxy)benzoate (2.2 g) were added thereto. The mixture was stirred at room temperature for 96 hours and partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was dried and concentrated under reduced pressure. The residue was dissolved in methanol and purified by RPHPLC to give the titled compound. Yield: 0.768 g (22%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[H-].[Na+].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].O>CN(C)C=O>[CH3:17][O:16][C:14]([CH:13]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[CH3:18])=[O:15]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1ccccc1C#N
Reaction time: 1 h
Yield: 98.7 %

Procedure:
2-Cyanophenol (1.0 g, 8.39 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 60% sodium hydride (0.40 g, 10 mmol) was added thereto under ice-cooling, followed by stirring for one hour. Methyl (±)-2-bromopropionate (1.03 ml, 9.23 mmol) was added to the mixture followed by stirring at room temperature for one night. After the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-[1-(methoxycarbonyl)ethoxy]benzonitrile (1.70 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([N+:20]([O-:22])=[O:21])=[CH:11][C:12]=2[S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.5 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00323 mol) in acetic anhydride is cooled with an ice bath, treated with nitric acid (0.15 mL, 0.00329 mol), warmed to room temperature, stirred for 20 hours and poured into water. The mixture is decanted and the insolubles are dissolved in ethyl acetate. The ethyl acetate solution is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an amber residue. Flash chromatography of the residue using silica gel and a 1:1 ethyl acetate/hexanes solution gives the title product as a tan solid (0.43 g, mp 174°-180° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([N:23]=[N+]=[N-])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)C.[H][H]>[Pd].CO>[C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH2:23])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n1C
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N)c(=O)n1C

Procedure:
A mixture of (R)-8-acetyl-3-(5-azidohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (200 mg, 0.534 mmol) and 10% palladium on carbon (50% water, 150 mg) in a solution of ethanol (50 ml) and methanol (10 ml) was treated with hydrogen gas (50 psi) on a Parr sharker at room temperature for 18 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-8-acetyl-3-(5-aminohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH2:25]([NH:27][CH3:28])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:27]([CH2:25][CH3:26])[CH3:28])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CCNC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(C)CC
Yield: 86.3 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.54 g (0.026 mol) of N-ethylmethylamine in 30 ml of DMF were reacted at room temperature for 16 hours affording a residue which was kugelrohr distilled at 80 Pa, pot temperature 104° C., to give 4.7 g of oil. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded 4.0 g of oil which was purified by kugelrohr distillation at 67 Pa, pot temperature 107° C., to give
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][C:18]#N)[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.Cl.CC[O:33]CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH:18]=[O:33])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CN(CC[C@H]1CC[C@H](CC#N)CC1)C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CC[C@H]1CC[C@H](CC=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 10.14 g (36.17 mmol) of trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 90 mL of CH2Cl2 were added 90 mL (108.5 mmol, 3 eq) of 1.2M DIBAH at −70-−78° C. The solution was stirred at that temperature for 4 h, 40 mL of 4M HCl were added carefully and the solution was slowly warmed to RT. Stirring was continued at RT for 10 min, and the substance was partioned between ether and 1M HCl. The organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with n-hexane: EtOAc 1:3 to yield 7.5 g (73%) of trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohexyl]-ethyl}-carbamic acid tert-butyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24].O1[CH2:30][CH2:29]OCC1>>[ClH:23].[ClH:24].[N:8]1([CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[CH2:30][CH2:29][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCCCCCl)cc2C1
Reactant: C1COCCO1
Agent: Cl
Product: c1cc2c(cc1OCCCCN1CCCCC1)CNCC2

Procedure:
7-(4-Piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride is prepared from 7-(4-chloro-butoxy)-3,4-dihydro-1-H-isoquinoline-2-carboxylic acid tert-butyl ester (600 mg, 1.5 mmol) and 4N HCl/dioxane (2.5 mL, 10 mmol) base in a manner substantially analogous to Procedure B to give the product (490 mg, 90% yld). MS(ES+)389.3 (M+H)+ free
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]([O:15]C)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].B(Br)(Br)Br.[OH-].[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]([OH:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCc1cc(F)c(C(=O)OC)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCc1cc(F)c(C(=O)O)cc1O
Temperature: -70 °C
Yield: 97.7 %

Procedure:
Methyl 2-fluoro-5-methoxy-4-propylbenzoate (1.27 g, 5.63 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to -70° C. Boron tribromide (1.64 mL, 16.9 mmol) was added and the temperature was slowly raised to 0° C. during 4.5 h. Methylene chloride (20 mL) and 2M NaOH (25 mL) were added and the mixture was stirred over-night at room temperature. Water (20 mL) was added, the phases separated and the aqueous phase was extracted with CH2Cl2 (20 mL) and acidified to pH 1 by concentrated HCl thus precipitating the acid. Ethyl acetate (50 mL) was added to the mixture and the phases separated. The aqueous phase was extracted by additional EtOAc (50 mL) and the combined organic phases were washed with brine (20 mL), dried (MgSO4) and evaporated yielding 2-fluoro-5-hydroxy-4-propylbenzoic acid (1.09 g) Mp: 134.5°-135.5° C. 1H NMR (DMSO-d6): d 12.88 (br, 1 H), 9.57 (br, 1 H), 7.23 (d, J=6.5 Hz, 1 H), 6.96 (d, J=11.6 Hz), 2.48 (t, J=7.5 Hz, 2 H), 1.53 (m, J=7.5 Hz, 2 H), 0.87 (t, J=7.4 HZ, 3 H). 13C NMR (DMSO-d6): δ 164.96 (d, J=3 Hz), 154.38 (d, J=248 Hz), 150.84 (d, J=2 Hz), 135.82 (d, J=7 Hz), 117.44 (d, J=24 Hz), 116.28 (d, J=11 Hz), 116.22, 31.38, 21.79, 13.65. MS (EI, 70 eV): m/z (rel.int) 198 (M+, 38).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[O:15][CH3:16])(C)(C)C>O1CCOCC1.CO>[CH3:16][O:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH2:8].[ClH:1]
Reactant: CO[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CO[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl(cis-2-methoxycyclohexyl)carbamate (0.17 g, 0.74 mmol) in methanol (0.5 mL). The reaction mixture was stirred at r.t. overnight. The volatiles were removed under reduced pressure to afford the desired product as HCl salt. Analytic LCMS (M+H)+: m/z=130.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1.[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH:15]([NH:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: CON=C(C(=O)O)c1nc(N)sc1C
Solvent: O=CO
Product: CON=C(C(=O)O)c1nc(NC=O)sc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-amino-5-methylthiazol-4yl)-2-methoxyiminoacetic acid (syn isomer, 2.6 g.), acetic anhydride (31 ml.) and formic acid (13 ml.) was stirred at room temperature for 2 hrs. and then evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then filtered. The filtrate was evaporated in vacuo. The oily residue was treated with n-hexane and diisopropyl ether, and the precipitates were collected by filtration to give 2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.8 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])=[O:30])([CH3:27])([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:24]([O:28][C:29](=[O:30])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:38])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[S:10])=[CH:4][CH:3]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1ccc(NC(=S)NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
Thiourea 4 (100 mg, 0.31 mmol, 1 equiv.) was stirred in dry CH2Cl2 (5 mL) under N2 atmosphere and acid 31 (106 mg, 0.46 mmol, 1.5 equiv.) was added, followed by bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (214 mg, 0.46 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (53 μL, 0.31 mmol, 1 equiv.). The reaction mixture was stirred at rt for 16 h then diluted with CH2Cl2 (20 mL) and washed with 1 M aqueous hydrochloric acid (1×10 mL), 1 M aqueous sodium hydroxide (1×10 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give a crude yellow oil which was purified with column chromatography on silica (25-50% ethyl acetate/petroleum ether) to give 32 (86 mg, 54%) as a colourless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].Cl[C:7]1[C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[NH:12][C:11]=2[C:10]([N+]([O-])=O)=[CH:9][CH:8]=1>CO.C1COCC1>[CH3:23][O:22][C:16]1[C:17]2[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:19]3[C:18]=2[C:13]([NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:20]=23)=[CH:14][CH:15]=1
Reactant: NNCCO
Reactant: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c3c(nn(CCO)c13)-c1ccccc1N2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.6 g of 2-hydroxyethyl hydrazine in 5 ml of methanol and 20 ml of THF was added over 1.5 hours to a mixture of 6.09 g of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone in 75 ml of methanol and 55 ml of THF, and the resulting suspension was stirred 20 hours at room temperature. The precipitate was coliected and recrystallized from DMSC-methanol, providing 9=methoxypyrazolo[3,4,5-kl]acridine-2(6H)ethanol, mp 275°-276 C.
Reaction SMILES: [C:1]([CH:3]([C:13]([C:15]1[C:16]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH2:33][OH:34])[C:17]=2[N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:14])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>N1C=CC=CC=1>[C:38]([CH2:37][CH2:36][C:35]([O:34][CH2:33][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH2:32][C:16]1[C:15]([C:13](=[O:14])[CH:3]([C:1]#[N:2])[C:4]([NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:5])=[N:19][N:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:17]=12)=[O:41])([OH:40])=[O:39]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1c(CO)cccc1-2
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1c(COC(=O)CCC(=O)O)cccc1-2
Temperature: 45 °C
Reaction time: 20 h
Yield: 63.2 %

Procedure:
2-cyano-3-(1,4-dihydro-5-hydroxymethyl-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (1.1 g) is reacted with succinic anhydride (0.8 g) in anhydrous pyridine (40 ml) under stirring at 45° C. for 20 hours. After cooling the reaction mixture is diluted in ice water and the precipitate is filtered and washed with water. Crystallization from CH2Cl2 /isopropanol yields 0.85 g of 3-[5-(3-carboxy-propanoyloxymethyl) -1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.