Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1.[NH2:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[O:26][C:25]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1>>[CH3:30][N:28]([CH2:27][C:25]1[O:26][C:22]([CH2:21][S:20][CH2:19][CH2:18][NH:17][C:3]2[NH:8][C:7](=[O:9])[C:6]([O:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:5][N:4]=2)=[CH:23][CH:24]=1)[CH3:29]
Reactant: CSc1ncc(Oc2cccnc2)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Oc3cccnc3)c(=O)[nH]2)o1
Yield: 49.7 %

Procedure:
A mixture of 2-(methylthio)-5-(3-pyridinyloxy)-4(3H)-pyrimidinone (1.18 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (2.14 g) was heated at 140° for 6 h. the residue was chromatographed (silica/ethyl acetate-methanol, 1:1) to give the title compound (1.0 g) as a yellow gum.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([NH:5][C:6]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:7]2)=[N:3][CH:2]=1>C(O)C.O1CCCC1.[Ni]>[N:1]1[CH:9]=[C:8]2[C:4]([NH:5][C:6]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:7]2)=[N:3][CH:2]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cncnc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4cncnc4[nH]3)cccc21
Reaction time: 20 h
Yield: 89.3 %

Procedure:
The procedure used in Example 6 is followed, in an autoclave, starting from 450 mg of 4-(9H-purin-8-yl)fluoren-9-one oxime (Z,E), obtained in the previous stage, in solution in a mixture of 25 ml of ethanol and 25 ml of tetrahydrofuran, in the presence of Raney activated nickel, under an initial hydrogen pressure of 1 bar, at 600 for 20 hours. After filtration of the catalyst over Celite, and concentration of the filtrate under reduced pressure, in this way, we obtain 384 mg of 4-(9H-purin-8-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige powder with the following characteristics:
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].O>O1CCCC1>[I:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)ncnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
4-Iodo-7H-pyrrolo[2,3-d]pyrimidine (352 mg, 1.44 mmol) in tetrahydrofuran (15 mL) cooled to 0° C. was mixed with sodium hydride (55 wt % dispersion in mineral oil, 75.5 mg, 1.73 mmol) and chlorotriisopropylsilane (0.37 mL, 1.7 mmol) and stirred at room temperature for 45 minutes. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/1 (v/v)) to give the title compound as a pale yellow oil (431 mg, yield 74%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:6][CH:14]([OH:15])[C:13]([OH:17])=[O:16])=[O:5]
Reactant: O=CC(=O)O
Reactant: NC(=O)c1c(F)cccc1F
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(O)C(=O)O)c1c(F)cccc1F
Yield: 52.5 %

Procedure:
A mixture of 50 g (0.318 mol) of 2,6-difluorobenzamide, 32 g (0.349 mol) of glyoxylic acid monohydrate and 200 mL of acetone was refluxed for 5 h. The reaction was cooled and solvents evaporated to give a white solid. It was triturated with cold acetone to afford 38.56 g of a white solid: mp 125°-127° C. 1H-NMR (DMSO-d6)δ9.55 (d, 1H), 7.50 (m, 1H), 7.15 (t,2H), 5.45 (d,1H)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCC(O)CC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and piperidin-4-ol under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.29 (d, 1H), 8.21 (m, 1H), 7.85 (m, 1H), 7.59 (m, 2H), 7.41 (m, 2H), 7.15 (d, 1H), 7.05 (d, 1H), 4.31 (t, 2H), 4.10 (m, 2H), 3.75 (m, 1H), 3.60 (t, 4H), 3.20 (m, 2H), 2.89 (m, 2H), 2.59 (m, 4H), 1.81 (m, 2H), 1.40 (m, 2H). MS: 477.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.O>C(OCC)(=O)C>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:10][C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
The mixture of 50.7 g (0.35 mol) 1,2-diamino-4,5-difluorobenzene, 55.1 g (0.35 mol) 4-chlorobenzoic acid and 507 g polyphosphoric acid was heated to 160° C. and stirred at this temperature for 90 min. After cooling to 55° C., 1000 mL water and 500 mL ethyl acetate were added. Under ice cooling ca 1000 mL 32% aqueous sodium hydroxide solution was added (pH ca 9). The suspension was filtered over dicalite and the filter cake was washed with 1.5 L ethyl acetate. The phases were separated and the aqueous phase was washed with 0.5 L ethyl acetate. The organic phases were washed with 1M aqueous sodium hydroxide solution and brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using a gradient of n-heptane:ethyl acetate (v/v, 4:1 to 1:1) as eluant. The fractions containing the product in pure form were pooled and evaporated. The remaining fractions were dissolved in ethyl acetate, washed twice with 1M aqueous sodium hydroxide solution and brine, the combined aqueous layers extracted once with ethyl acetate and the combined organic layers dried over magnesium sulfate and filtered. Chromatography over silica gel afforded a second batch of compound. Total yield: 75 g (80%) light yellow solid. MS (ES+): 265 (M+H).
Reaction SMILES: CC(C)=O.Cl[C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1.[CH:19]12[O:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2>C(N(CC)CC)C>[Cl:12][C:10]1[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=[C:6]([N:21]2[CH2:20][CH:19]3[O:26][CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[N:11]=1
Reactant: C1CC2CNCC1O2
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCOCC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred acetone/crushed ice suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3 ml) was added and stirred at room temperature for 6 hours. At the end, the separated solid was filtered and washed with water. The crude product was found to be pure enough for further transformations. Yield: 2.0 g (99%); mp. 118; (M+H) 313.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([F:12])[F:11])(=[O:9])[O:6]CC.Cl>>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([F:12])[F:11])(=[O:6])[OH:9]
Reactant: CCOP(=O)(CCCN)C(F)F
Agent: Cl
Product: NCCCP(=O)(O)C(F)F

Procedure:
A mixture of 520 mg (2.6 mmol) of ethyl P-(3-aminopropyl)-P-difluoromethyl-phosphinate and 5 ml of 12M hydrochloric acid is refluxed for 3 hours and then evaporated to dryness. The residue is dissolved in 5 ml of methanol. To the stirred solution 25 ml of epoxypropane are added dropwise, upon which spontaneous crystallisation occurs. The crystals are collected and dried yielding P-(3-aminopropyl)-P-difluoromethyl-phosphinic acid of m.p. 261°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([CH3:26])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([CH3:26])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([C:9]1[C:10]([Cl:17])=[N:11][C:12]([Cl:16])=[N:13][C:14]=1Cl)[CH3:8])(=O)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>>[Cl:16][C:12]1[N:11]=[C:10]([Cl:17])[C:9]2[C@@H:7]([CH3:8])[CH2:6][N:27]([CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:14]=2[N:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: C[C@@H](COS(C)(=O)=O)c1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C[C@H](C)c3c(Cl)nc(Cl)nc32)cc1
Yield: 74 %

Procedure:
(R)-2,4-dichloro-7-(4-methoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was prepared from (R)-2-(2,4,6-trichloropyrimidin-5-yl)propyl methanesulfonate (60 mg, 0.188 mmol), (4-methoxyphenyl)methanamine (39 mg, 0.28 mmol) and triethyl amine (38 mg, 0.375 mmol), and isolated as a yellow (45 mg, yield 74%). 1H NMR (400 MHz, CDCl3) δ ppm 7.16-7.19 (d, 2H, J=8.8 Hz), 6.86-6.88 (d, 2H, J=8.4 Hz), 4.54 (s, 2H), 3.80 (s, 3H), 3.66-3.71 (t, 1H, J=6.0 Hz), 3.33-3.36 (m, 1H), 3.08-3.12 (dd, 1H, J=4.4 Hz, 10.0 Hz), 1.29-1.31 (d, 3H, J=6.8 Hz).
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29]>C(#N)C>[N+:28]([C:16]1[CH:17]=[C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:11][CH:8]([CH2:9][O:10][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:26])([F:27])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29])[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:30])=[O:29]
Reactant: OCC(O)CN1CCCCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1OCC(CN1CCCCC1)Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Using the same procedure as for example 54, a mixture of 3-piperidino-1,2-propanediol (40 mg, 0.25 mmol), sodium hydride (60%, 30 mg) and 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (174 mg, 0.6 mmol) in acetonitrile (1 mL+0.6 mL) was heated to reflux for 18 hours, worked-up and purified on silica gel to give the title compound. MS +ve APCI 666 [M+1].
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[C:22]([NH2:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.[CH3:37][O:38][C:39](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]4[NH:27][C:37]([O:38][CH3:39])=[N:28][C:22]=4[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: COC(OC)(OC)OC
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(OC)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 1.00 g (2.02 mmol) (R)-2-(3,4-diamino-5-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 4a), 2.0 mL (15.0 mmol) tetramethoxymethane and 40 mg p-toluenesulphonic acid-monohydrate in 20 mL MeOH was refluxed for 1 h. The mixture was evaporated down i.vac. and the residue was purified by chromatography (Alox, activity stage II-III, DCM/MeOH 20:1).
Reaction SMILES: I[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:24])([F:23])C(O)=O.[Na]>CN1CCCC1=O.[Cu]I>[F:18][C:19]([F:24])([F:23])[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Reactant: O=C(O)C(F)(F)F
Agent: [Cu]I
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1=Cc2cccc(C(F)(F)F)c2OCC1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (1.00 g), trifluoroacetic acid, sodium salt (1.58 g), and copper(I) iodide (1.11 g) in 1-methyl-2-pyrrolidinone (10 ml) was stirred at 160° C. under nitrogen atmosphere for 6 hours and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 2,3-dihydro-9-trifluoromethyl-1-benzoxepin-4-carboxylate (0.93 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1CCN1CCCC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.43 g, 2.575 mmol) and K2CO3 (1.06 g, 7.726 mmol) in dry DMF (5 mL) was stirred at 100° C. overnight (18 hours). The reaction was brought to room temperature, diluted with water (100 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.49 g, 65%) as a solid. 1H NMR (DMSO-d6) δ 1.62-1.70 (m, 4H), 2.46-2.54 (m, 4H, merged with DMSO-d6 resonance), 2.60 (t, 2H, J=6.9 Hz), 4.08 (t, 2H, J=6.9 Hz), 4.80 (s, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.80 (d, 1H, J=2.4 Hz), 7.96 (dd, 1H, J=2.7, 9.0 Hz); ESI-MS (m/z, %): 292 (MH+, 100).
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[OH:1][CH:2]([CH2:24][O:25][C:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
A solution of 2 (21 mmol) in 80 ml of dichloromethane/pyridine (1:1) is added dropwise with triphenylmethyl chloride (27 mmol) and stirred at room temperature for 48 hours. The solvent is removed, and the residue is added twice with 50 ml of toluene and concentrated. The residue is diluted with 100 ml of H2O and extracted three times with 50 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by chromatography on silica gel using heptane/ethyl acetate (5:1). Yield: 88% of a colorless oil.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 2,3-dibromopropionate (142.7 g, 0.549 mol) in dry toluene (2000 mL) was added N,N′-dibenzylethylene diamine (132 g, 0.549 mol), followed by triethylamine (110.8 g, 1.098 mol), under N2 at 40° C. (a dense white precipitate formed immediately, thus good stirring was necessary). The mixture was heated at 80° C. overnight, cooled and filtered. The filtrate was then washed with H2O, dried over MgSO4, and concentrated under reduced pressure. The residue oil was taken on to the next step without further purification (GC-MS shows one peak at 6.79) or purified by column chromatography (EtOAc/hexane 1:4). Weight of crude product: 169.6 g (91%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl[C:11]1[N:16]=[C:15](Cl)[C:14]([CH2:18][CH3:19])=[C:13]([Cl:20])[N:12]=1>O>[CH2:1]([O:8][C:11]1[N:16]=[C:15]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([CH2:18][CH3:19])=[C:13]([Cl:20])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCc1c(Cl)nc(Cl)nc1Cl
Agent: [Na]
Solvent: O
Product: CCc1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of benzyl alcohol (80 mL) in water bath, was added sodium metal (2.17 g, 94.6 mmol) under nitrogen atmosphere. After complete reaction of sodium metal, the mixture was cooled in an ice bath and 2,4,6-trichloro-5-ethyl-pyrimidine (10.5 g, 49.6 mmol) was added in portions. After stirring for 30 min in an ice bath, the reaction mixture was stirred at room temperature for overnight. Excess benzyl alcohol was evaporated in vacuo and the residue was dissolved in ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (4:96)) to give 14 g (80%) of a white solid; m.p. 53-54° C.; 1H NMR (200 MHz, CDCl3) δ: 1.14 (3H, t, J=7.4 Hz), 2.70 (2H, q, J=7.4 Hz), 5.41 (2H, s), 5.45 (2H, s), 7.34-7.53 (10H, m); m/z (EI): 354 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=O)[CH:16]=1.Cl.[NH2:23][OH:24].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[N:23][OH:24])[CH:16]=1
Reactant: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2=CC(=NO)CCC2)c(OCOC)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (200 mg), hydroxylamine hydrochloride (72 mg) and triethylamine (0.14 ml) were heated under reflux in ethanol (10 ml). After 3 hr, the cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil (206 mg, 99%). m/z (ES+) 308 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:27])[CH2:19][CH2:18][CH2:17][CH:16]2[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:27][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])=[CH:10][CH:11]=2)[CH2:19][CH2:18][CH2:17][CH:16]1[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22]
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCN)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1ccc(C2(O)CCCC2NS(=O)(=O)C(C)C)cc1
Temperature: 0 °C

Procedure:
In a 100 mL 3 neck flask fitted with a stirrer and thermometer, acetyl chloride (63 mg, 1.2 eq) is added dropwise to {2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine (230 mg, 0.67 mmol) and triethylamine (102 mg, 1.5 eq) in CH2Cl2 (40 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and stirred for 2 hours. The reaction is then diluted with CH2Cl2 (50 mL) and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum to yield the product. This material is purified via silica gel chromatography employing the Chromatotron® and using 2000 micron rotor while eluting with a suitable eluent, such as hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:22]=[CH:23][C:11]=2[N:10]=1.[Mn]([O-])(=O)(=O)=[O:31].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([OH:31])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24](=[O:25])(=[O:26])[N:27]([CH3:29])[CH3:28])[N:22]=[CH:23][C:11]=2[N:10]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C(=O)O)ccc3c21
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A 250 ml round-bottomed flask is charged with 1.41 g of 5-(2,6-difluorophenyl)-7-formyl-N,N-dimethyl-1H-pyrazolo[4,3-c]isoquinoline-1-sulphonamide in 124 ml of acetone. 1.07 g of potassium permanganate in solution in 62 ml of water are added. After 1 h at RT, the acetone is evaporated and then the mixture is acidified to a pH of 1 by addition of 5N hydrochloric acid. The mixture is extracted with ethyl acetate and the organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP to give 1.46 g of 5-(2,6-difluorophenyl)-1-(dimethylsulphamoyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylic acid (yellow solid). LC-MS-DAD-ELSD: 433 (+)=(M+H)(+).