Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48])C>CCOCC>[F:33][C:30]([F:31])([F:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:48][C@H:47]([C:46]([OH:50])=[O:45])[CH3:49])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of 4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]2)[N:13]=3)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:21]2)[N:13]=3)[CH:7]=[CH:6][C:3]=1[CH2:4][N:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1
Reactant: O=C(O)C1CNC1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1CN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (22.6 mg, 0.061 mmol), azetidine-3-carboxylic acid (31 mg, 0.305 mmol), and acetic acid (28 μL, 0.488 mmol) in 1:1 CH2Cl2/MeOH (2.0 mL) was stirred at 25° C. for 1 h. Sodium cyanoborohydride (6.9 mg, 0.110 mmol) was then added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo, dissolved in DMSO (2 mL)+trifluoroacetic acid (20 μL), filtered, and purified by rpHPLC (10-100% acetonitrile/water+0.1% TFA) to provide 1-((2-methyl-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 455.2; Observed: 456.1 (M++1).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([O-:13])=[O:12].Cl>N1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([NH:17][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:18]=[CH:19][CH:20]=1)([O-:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
Benzenesulfonyl chloride (6.01 mL, 46.8 mmol) was added to a solution of 3-nitroaniline (6.47 g, 46.8 mmol) in pyridine (50 mL) at room temperature. The mixture was heated to 100° C. for 1 h. Most of the pyridine was evaporated under reduced pressure. The resulting brown oil was dissolved in CH2Cl2 (100 mL) and washed with aqueous HCl (150 mL, 50 mmol). A tan solid precipitated out from the acidic aqueous phase. The solid was collected by filtration, washed with CH2Cl2 and dried under vacuum (10.41 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (1H, s), 7.93 (1H, s), 7.85-7.89 (1H, m), 7.79-7.83 (2H, m), 7.61-7.67 (1H, m), 7.49-7.61 (4H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)=[O:8].OO.S([O-])(O)=[O:22].[Na+].C(OO)=O>C(O)=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][S:12]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)=[O:22])=[O:8]
Reactant: Cn1nnnc1SCCCS(=O)c1ccccn1
Reactant: O=S([O-])O
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S(=O)CCCS(=O)c1ccccn1
Reaction time: 5 h

Procedure:
3-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiopropyl 2-pyridyl sulfoxide (2.8 g) is dissolved in formic acid (20 ml) and thereto is added with stirring 30% hydrogen peroxide (1.3 g) at room temperature, and the mixture is stirred for 5 hours. To the mixture is added sodium hydrogen sulfite under ice-cooling in order to decompose excess performic acid. Water is added to the resulting mixture and it is extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography [Wakogel C-200, eluting agent, chloroform-methanol (50:1)] to give 3-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfinylpropyl 2-pyridyl sulfoxide (0.8 g) as colorless liquid, nD28.5 =1.5795.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:41][C:40]([SH:42])=[N:39][N:38]=2)=[CH:33][CH:32]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[O:41][C:40]([SH:42])=[N:39][N:38]=5)=[CH:35][CH:36]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc(-c2nnc(S)o2)cc1
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(-c5nnc(S)o5)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 11.3 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol) and 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol (23 mg, 0.12 mmol) in pyridine (10 mL) was added POCl3 (0.3 mL, 3.29 mmol) at 0° C., the reaction mixture was stirred at room temperature for 6 hours, a sat. NaHCO3 solution was added slowly, the solvent was removed in vacuo, methanol (20 mL) were added and filtrated. The filtrate was collected, concentrated and purified by a silica column chromatography (silica gel 200-300 mesh, eluting with dichloromethane:methanol=40:1) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)piperidine-3-carboxamide (8.0 mg, 11.3%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.42 (s, 1H), 9.67 (s, 1H), 8.86 (s, 1H), 7.86-7.78 (m, 4H), 7.66 (s, 1H), 7.35 (d, 1H, J=8.7 Hz), 6.81 (brs, 1H), 4.81 (d, 1H, J=11.7 Hz), 4.66 (d, 1H, J=13.2 Hz), 3.69 (s, 3H), 3.63 (s, 3H), 3.15-3.07 (m, 1H), 3.01-2.93 (m, 1H), 2.73-2.61 (m, 1H), 2.07-1.74 (m, 3H), 1.78-1.74 (m, 1H). LC-MS: 591 [M+H]+, tR=1.56 min. HPLC: 97.80% at 214 nm, 97.26% at 254 nm, tR=5.91 min
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CCCN2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a stirred solution of methyl 2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (262.5 mg, 0.870 mmol) in CH2Cl2 (5.3 mL) was added TFA (1.1 mL) at 0° C., and the resulting mixture was stirred at room temp for 1 hr. The solvent was removed under a reduced pressure and the residue was made basic by the addition of the 1 N NaOH, and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 173.1 mg (94%) methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ 1.49–1.58 (ddt, J=6.8, 8.8 Hz, 1H), 1.72–1.87 (m, 2H), 1.90–1.99 (m, 1H), 2.92–3.05 (m, 2H), 3.50–3.57 (ddd, J=4.4,7.3, 15.1 Hz, 1H), 3.91 (s, 3H), 4.23 (dd, J=7.8, 10.7 Hz, 1H), 4.38 (dd, J=4.4, 10.7 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 8.15 (dd, J=2.4, 8.8 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H); MS (FAB) m/z 237 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-:21].[K+].[K+].ClCCl.[C:29](#[N:31])[CH3:30]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:31][C:29](=[O:21])[CH3:30])([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(O)CCN(Cc2ccccc2)C1
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)NC1(C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 1-benzyl-3-methylpyrrolidin-3-ol (1.0 g, 5.2 mmol) in acetonitrile (10 mL) at 0° C., was added concentrated sulfuric acid (10 mL) slowly. After being stirred for 16 hours at room temperature, the reaction mixture was poured into ice-water. After the reaction mixture was adjusted to pH 7 with a saturated aqueous solution of potassium carbonate, the resulting mixture was exacted with dichloromethane (200 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vauo. The residue was purified by preparative HPLC to afford 600 mg of the product (yield was 50%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:30]([NH:33][CH2:34][CH2:35]O)(=[O:32])[CH3:31]>ClCCCl.C1COCC1>[C:30]([NH:33][CH2:34][CH2:35][O:10][C:9](=[O:11])[CH:8]([O:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:25])[F:1])=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)NCCO
Reactant: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)NCCOC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a slurry of acid 39 (25.8 g, 0.071 mol) in anhydrous 1,2-dichloroethane (380 mL) was added thionyl chloride (16.0 mL, 0.21 mol), and then the resulting mixture was refluxed for 2 h. The mixture was cooled to rt, diluted with dry THF (150 mL) until the cloudy mixture turned clear, and then N-acetylethanolamine (39.12 g, 0.38 mol) was added. The resulting solution was stirred at rt overnight. The reaction was quenched with sat. NaHCO3 carefully, diluted with EtOAc, and washed with water. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was recrystallized from iPrOH/hexanes (11 mL/31.5 mL) to afford pure product 136 (22.78 g, 71%) as a off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.89 (1H, s), 7.80 (1H, d), 7.69 (1H, d), 7.57-7.61 (3H, t), 7.06 (2H, t), 5.78 (1H, s), 5.27 (1H, br), 4.24 (2H, m), 3.45 (2H, dd), 1.81 (3H, s) ppm.
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=[O:15])#[CH:2].Cl.BrC1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(NCC)C.O.[Cu]I>[CH3:14][O:13][C:12]1[C:3]([CH2:1][C:2]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][N:6]=[CH:5]2
Reactant: Brc1ccncc1
Reactant: C#Cc1c(OC)ccc2c(=O)[nH]ncc12
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CCNCC
Product: COc1ccc2c(=O)[nH]ncc2c1Cc1ccncc1
Temperature: 75 °C
Yield: 89.2 %

Procedure:
A suspension of 5-ethynyl-6-methoxy-2H-phthalazin-1-one (1.9 g, 9.49 mmoles), prepared as described in example 140, 4-bromopyridine hydrochloride (2.214 g, 11.39 mmoles), bis(triphenylphosphine)PdCl2 (133 mg, 0.1998 mmole) and CuI (36 mg, 0.1898 mmole) in diethylamine (40 ml) was heated at 75° C. for 1 hour, cooled, diluted with water (40 ml) and the solid was filtered after 30 minutes under stirring. The solid was suspended in acetone, stirred for 15 minutes, filtered again and dried in oven at 45° C. under vacuum giving 2.263 g of the title compound (yield: 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:23][NH:22][CH2:21]3)=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:33]#N.[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:21][N:22]([CH3:33])[CH2:23]3)=[N:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CNC3)o2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC(c2nnc(C(=C3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)o2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-(azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.029 g, 0.074 mmol) in MeOH (5 mL) was added formaldehyde (0.322 mL, 57% solution in H2O) dropwise at rt. A solution of NaCNBH3 (0.026 g, 0.415 mmol) in MeOH (0.3 mL) was then added and the solution was stirred at rt for 15 min. The resulting mixture was poured into H2O and extracted with EtOAc (×3), and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (NH4OAc) to afford the title compound (0.012 g, 17%) as a colorless solid:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)C.[ClH:21]>[OH-].[Na+]>[OH2:3].[ClH:21].[NH:16]1[CH:17]=[CH:18][N:19]=[C:15]1[CH2:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:20])=[O:3].[NH:16]1[CH:17]=[CH:18][N:19]=[C:15]1[CH2:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:20])=[O:3].[ClH:21]
Reactant: CCOC(=O)COc1ccc(C)cc1Cc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCC(=O)O)c(Cc2ncc[nH]2)c1
Product: O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(1-imidazolylmethyl)-4-methyl-phenoxyacetic acid ethyl ester (1.0 g) and 10 ml of 2.5N sodium hydroxide solution was stirred at room temperature overnight. The solution was acidified with dilute hydrochloric acid and evaporated. The residue was extracted with boiling ethanol (2×50 ml) and the extracts were evaporated to give a solid which was crystallised from ethanol/ether to give 2-(1-imidazolylmethyl)-4-methyl-phenoxyacetic acid hydrochloride hemihydrate (0.50 g), m.p. 198°-201° C. Found: C, 53.69, H, 5.26, N, 9.45. C13H14N2O3.HCl.1/2H2O requires: C, 53.52, H, 5.53, N, 9.60%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[C:19]([O:23][C:24](=[O:33])[N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C=O)C.ClCCl>[C:19]([O:23][C:24](=[O:33])[N:25]([CH:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH2:30][CH2:31]1)[CH3:32])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CC1
Temperature: 130 °C
Yield: 87.9 %

Procedure:
Add 1-chloro-4-(4-fluorophenyl)-phthalazine (3.00 g, 11.6 mmol) to a solution of methyl-piperidin-4-yl-carbamic acid tert-butyl ester (2.98 g, 13.9 mmol) and triethylamine (3.52 g., 34.8 mmol) in DMF (30 mL). Heat at 130° C. for 3 days. Dissolve the reaction mixture in dichloromethane and wash with brine. Dry the organic phase with sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography (20:5:1, hexane:ethyl acetate: 2 M ammonia in methanol) to yield the title compound as a solid (4.45 g, 88%). ES/MS m/z 437.2 (M+1).
Reaction SMILES: I.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[NH:14])SC)[CH:6]=[CH:7][C:8]=1[CH3:9].CS(O)(=O)=O.[NH2:20][CH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[N:26]([CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:33]1=[O:39])[CH2:25]2.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[N:26]([CH:32]2[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[CH2:25]3)=[NH:14])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CSC(=N)Nc1ccc(C)c(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=N)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Product: Cl
Yield: 43.4 %

Procedure:
In a microwave vial fitted with a stir bar, 1-(3-chloro-4-methyl-phenyl)-2-methyl-isothiourea hydroiodide (597 mg, 1.74 mmol), 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (560 mg, 1.52 mmol), and DIEA (1.1 mL, 6.06 mmol) were combined in anhydrous DMF (5 mL). The vial was sealed and irradiated in a microwave for 30 min at 120° C. To the reaction mixture was added an additional 100 mg of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate and the reaction was irradiated for 30 min at 120° C. This process was repeated twice more to consume all of the 1-(3-chloro-4-methyl-phenyl)-2-methyl-isothiourea hydroiodide starting material as it was found co-elute with the desired product on LCMS. The reaction mixture was acidified with acetic acid and the volatiles were evaporated in vacuo. The residue was dissolved in minimal DMF, filtered, and purified using C-18 preparatory HPLC. To the combined fractions containing the desired product, 1 N HCl was added and the solvents removed in vacuo. The obtained white solid was dissolved in minimal water and lyophilized to give 180 mg (27% yield) of N-(3-chloro-4-methyl-phenyl)-N′-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-guanidine hydrochloride: HPLC:Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 3.73 min (97.4%); mp: >400° C.; 1H NMR (DMSO-d6) 1.91-2.09 (m, 1H, CHH), 2.33 (s, 3H, CH3), 2.41 (dd, J=4.3, 13.2 Hz, 1H, CHH), 2.54-2.68 (m, 1H, CHH), 2.80-3.05 (m, 1H, CHH), 4.21-4.56 (m, 2H, CH2), 4.66 (d, J=5.7 Hz, 2H, CH2), 5.13 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.14 (dd, J=1.9, 8.1 Hz, 1H, Ar), 7.34 (d, J=1.9 Hz, 1H, Ar), 7.42 (d, J=8.1 Hz, 1H, Ar), 7.51 (d, J=7.9 Hz, 1H, Ar), 7.61 (s, 1H, Ar), 7.76 (d, J=7.7 Hz, 1H, Ar), 7.98 (br. s., 1H, NH), 8.62 (br. s., 1H, NH), 10.16 (s, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) 21.04, 24.19, 32.95, 46.33, 49.85, 54.03, 124.13, 125.48, 125.79, 127.28, 129.17, 132.57, 134.20, 135.82, 135.95, 136.64, 143.17, 144.68, 156.84, 170.94, 173.00, 175.82; LCMS: MH=440, 442; Anal Calcd for C22H23Cl2N5O3+2.3 H2O+1.9 HCl+0.2 HCOOH: C, 44.72; H, 5.05; N, 11.74; Cl, 23.19. Found: C, 44.55; H, 4.71; N, 11.48; Cl, 22.92.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])#[N:16]>C1COCC1>[OH:21][CH:20]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9])[C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(C=O)c1
Reactant: OCc1cnccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2ccncc2CO)c1
Reaction time: 0.25 h

Procedure:
To a solution of (4-bromo-pyridin-3-yl)-methanol (20 mg, 0.11 mmol) in THF (1 mL) at −78° C. was added dropwise 2. 5M n-butyllithium (0.22 mL). After 15 min, a solution of 3-cyanobenzaldehyde (69 mg) in THF (0.5 mL) was added. The reaction mixture was stirred for 15 min, then quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[hydroxy-(3-hydroxymethyl-pyridin-4-yl)-methyl]-benzonitrile as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:28][C:22]1([CH3:29])[C:21]2[C:26](=[CH:27][C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)=[CH:19][CH:20]=2)[O:25][CH2:24][CH2:23]1
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCC(C=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)OCCC2(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of 4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid methyl ester (0.1 g, 0.25 mmole) in 25 mL of a 4:1 THF/methanol mixture was treated with a solution of 0.1 g of lithium hydroxide monohydrate in 5 mL of water. The reaction mixture was stirred at 40° C. for 2 hours, concentrated in vacuo and the pH adjusted to 3-4 with 1N HCl solution. The mixture was extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 0.06 g of 4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid as a colorless glassy oil. MS (EI): (M−−1): 391.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([O:24][CH3:25])[CH:19]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([O:24][CH3:25])[CH:19]([CH2:26][C:27]([OH:29])=[O:28])[CH2:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(COc2ccc3c(c2)CC(CC(=O)OCC)C3OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCOc1ccc(COc2ccc3c(c2)CC(CC(=O)O)C3OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
In 1 ml of tetrahydrofuran and 8 ml of methanol were dissolved 220 mg of ethyl 5-(p-heptyloxybenzyloxy)-1-methoxy-2-indaneacetate obtained in Example 4. After 1 ml of a 5% aqueous sodium hydroxide solution was added to the solution, the mixture was stirred at room temperature for 8 hours. After diluting with water, the system was rendered acidic with hydrochloric acid followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The obtained crystalline residue was recrystallized from ether-pentane to obtain 150 mg of 5-(p-heptyloxybenzyloxy)-1-methoxy-2-indaneacetic acid.
Reaction SMILES: [O:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[NH2:12][C:9]([CH3:10])=[CH:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccccc1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(N)=COc1ccccc1
Reaction time: 24 h

Procedure:
0.2 mol of phenoxyacetone in 200 ml of tetrahydrofuran is saturated at reflux temperature with ammonia gas with the addition of 0.2 g of p-toluene sulphonic acid. The mixture is allowed to stand at room temperature for 24 hours and the solvent is then removed by evaporation in vacuo. The evaporation residue is employed crude in the reaction of Example 5B.