Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
1-Benzhydryl-3-azetidinecarboxylic acid (3.12 g) was suspended in tetrahydrofuran (60 ml) and cooled under a nitrogen atmosphere in an ice-ethanol bath. Triethylamine (1.96 ml) was added dropwise, and a solution of ethyl chlorocarbonate (1.34 ml) in tetrahydrofuran (5 ml) was added dropwise over 20 min. After the dropwise addition, stirring was carried out at the same temperature for 30 min. The reaction mixture was filtered and washed with tetrahydrofuran (30 ml). The filtrate was added dropwise over 15 min to an aqueous (15 ml) solution of sodium borohydride (1.33 g) cooled in an ice water bath. Upon completion of the dropwise addition, the reaction mixture was stirred at room temperature. To the reaction mixture was gradually added 1N hydrochloric acid (35 ml) to decompose excess sodium borohydride, and a 1N aqueous solution of sodium hydroxide (35 ml) was added. This was extracted with ethyl acetate (100 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated, and the residue was dried under reduced pressure to provide the titled compound as a pale brown solid (1.59 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[N:22]=[C:23]=[O:24]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:22][C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:24]
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc2ccccc2c1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 2-naphthyl isocyanate. m/z (ES+) 314 (M+H)+.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].Cl.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])=[CH:18][CH:17]=3)=[O:16])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@@H]4C(C)C)cc3)CC2)c(C)c1
Yield: 69.3 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (S)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (496 mg) described in Preparation Example 80 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (583 mg) was obtained.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH:6]=[N:5][N:4]=[N:3]1.[OH-].[Na+].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.C(OCC)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[N:5][N:4]=[N:3]3)=[CH:18][CH:17]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCCCOc1ccc(-n2cnnn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(NCCCCOc1ccc(-n2cnnn2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.7 g of 4-[4-(1H-tetrazol-1-yl)phenoxy]butaneamine hydrochloride (Example 39) in 100 ml of water is treated successively with 3.5 ml of 10N NaOH and a solution of 2.7 g of 4-bromobenzenesulfonyl chloride in 100 ml of diethyl ether. The mixture is stirred at room temperature for 1.5 hours, the precipitate collected, washed with diethyl ether and water, and air dried. Recrystallization from ethanol gives the pure compound, m.p. 109°-110° C.; yield, 1.6 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:13]([O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 92.4 %

Procedure:
5-Bromo-2-tert-butylphenol (1.08 g, 4.71 mmol), benzyl bromide (0.69 mL, 5.7 mmol) and Cs2CO3(2.3 g, 7.1 mmol) were added to 23.6 mL of acetonitrile and stirred at room temperature for 64 hours. The reaction mixture was filtered and concentrated to dryness. Purification by FCC resulted in title compound (1.39 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]2)=[O:20])[C:6]([C:9](O)=[O:10])=[N:7][CH:8]=1.[Cl-].[NH4+].Cl.C[N:35](C)CCCN=C=N.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:22][CH2:23][C@H:24]([C:27]([F:28])([F:29])[F:30])[CH2:25][CH2:26]2)=[O:20])[C:6]([C:9]([NH2:35])=[O:10])=[N:7][CH:8]=1
Reactant: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cnc(C(N)=O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (150 mg, 0.35 mmol, EXAMPLE 31 Step 4) and ammonium chloride (56 mg, 1.05 mmol) in dichloromethane (5 mL) were added 1-ethyl-3-((3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (100 mg, 0.52 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (53 mg, 0.35 mmol) and triethylamine (176 mg, 1.74 mmol) respectively. After being stirred at room temperature for 24 h, water was added to the mixture. The mixture was extracted with dichloromethane, and the extract was dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by NH gel column chromatography (methanol/dichloromethane 1:30) followed by preparative high pressure liquid chromatography (prep. HPLC) (acetonitrile/0.01% aq. ammonia 96:4 to 4:96) to afford 75 mg (50%) of the title compound as an amorphous powder.
Reaction SMILES: CCCCCC.[P:7]([S:13][CH3:14])([S:9][CH:10]([CH3:12])[CH3:11])Cl.[CH2:15]([OH:17])[CH3:16]>C(N(CC)CC)C>[P:7]([S:13][CH3:14])([S:9][CH:10]([CH3:12])[CH3:11])[O:17][CH2:15][CH3:16]
Reactant: CCO
Reactant: CSP(Cl)SC(C)C
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOP(SC)SC(C)C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Into 20 ml of hexane, was dissolved 9.4 g of S-isopropyl S-methyl phosphorochloridodithioite. To the solution was added dropwise at 0° to 5° C. a mixture of 2.8 g of ethanol and 6.1 g of triethylamine. The resulting reactant mixture was stirred at 0° to 5° C. for 2 hours. The reaction was carried out under a nitrogen atmosphere to prevent oxidation. After removal of triethylamine hydrochloride by filtration, the filtrate was concentrated to obtain 9.4 g of O-ethyl S-isopropyl S-methyl phosphorodithioite. This product was dissolved in 20 ml of benzene and heated under reflux. To the solution, while being kept under reflux, was added dropwise 5.9 g of 30% aqueous hydrogen peroxide. The mixture was stirred at 80° C. for one hour and then left standing to cool down. The organic layer was washed twice with 20 g of a 5% aqueous sodium hydroxide solution and then twice with water. Th benzene was removed under reduced pressure, leaving behind 9.1 g of a reaction product which, on silica gel column chromatography, yielded 8.7 g of O-ethyl S-isopropyl S-methyl phosphorodithiolate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:23]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:23]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@H](C=CCCCCc1ccc2c(n1)NCCCC2)c1cnc(C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H](CCCCCCc1ccc2c(n1)NCCCC2)c1cnc(C)nc1

Procedure:
A mixture of 8-13 (0.48 g, 1.36 mmol), 10% Pd/C (10 mL), and ethanol (10 mL) was stirred under a balloon of hydrogen for 4 hours. Filtration and concentration gave 8-14 as a yellow oil.
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].Br[C:7]1[CH:8]=[C:9]([CH2:14][OH:15])[CH:10]=[C:11]([F:13])[CH:12]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:13][C:11]1[CH:10]=[C:9]([CH2:14][OH:15])[CH:8]=[C:7]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:12]=1
Reactant: CS(=O)[O-]
Reactant: OCc1cc(F)cc(Br)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(F)cc(CO)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 48.2 %

Procedure:
Methanesulphinic acid sodium salt (748 mg, 7.33 mmol) was added to (3-bromo-5-fluorophenyl)methanol (501 mg, 2.44 mmol) and copper(I) iodide (0.248 mL, 7.33 mmol) in DMSO (12 mL) under nitrogen. The resulting mixture was stirred at 90° C. for 3 days. The reaction mixture was diluted with EtOAc (300 mL), then filtered. The filtrate was washed sequentially with water (200 mL) and saturated brine (2×200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford [3-fluoro-5-(methylsulfonyl)phenyl]methanol (240 mg, 48.1%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:5][C:4]=2[N:3]=1.[ClH:35]>>[ClH:35].[ClH:35].[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][CH2:26][NH2:27])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Agent: Cl
Product: CCOCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC(C)(C)O
Temperature: 65 °C

Procedure:
tert-Butyl 2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (1.95 g, 4.12 mmol; prepared in Example 562) was slurried in 4.0 M ethanolic hydrogen chloride (15 mL). The reaction was heated at 65° C. for 1.75 hours during which time the starting material dissolved and a precipitate subsequently formed. The reaction mixture was cooled to ambient temperature and the solid was filtered, washed with ethanol, and dried to provide 1.49 g of 1-[4-amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol dihydrochloride as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]([OH:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]([O:18][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C(=O)OCC)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of ethyl 6-((2,4-dichlorobenzyl)oxy)-3-hydroxy-1-benzothiophene-2-carboxylate (200 mg) in DMF (dry) (5.0 mL) were added K2CO3 (104 mg) and ethyl 2-bromoacetate (0.084 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (152.7 mg).
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:22])[C:10]([C:12]1[C:20]2[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O.[Cl:23][C:24]1[C:33]([CH2:34][C:35]([NH2:37])=[O:36])=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH2:38][N:39]([CH3:41])[CH3:40])=[N:31]2)=[CH:26][CH:25]=1.[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[Cl:23][C:24]1[C:33]([C:34]2[C:35](=[O:36])[NH:37][C:9](=[O:22])[C:10]=2[C:12]2[C:20]3[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH2:38][N:39]([CH3:40])[CH3:41])=[N:31]2)=[CH:26][CH:25]=1
Reactant: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2n1
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc2c(C3=C(c4c(Cl)ccc5ccc(CN(C)C)nc45)C(=O)NC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.60 ml, 0.60 mmol, 3.0 equiv) was added at room temperature under an atmosphere of argon to a solution of (7-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (65 mg, 0.30 mmol, 1.5 equiv) and of 2-(7-chloro-2-dimethylaminomethyl-quinolin-8-yl)-acetamide (55 mg, 0.20 mmol) in anhydrous tetrahydrofuran (2.0 ml, dried over molecular sieves). The reaction mixture was stirred for 15 minutes at room temperature. It was then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC afforded the title compound (64 mg, 58%) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ=11.90 (br s, 1H), 11.18 (s, 1H), 9.72 (br s, 1H), 8.59 (d, J=8.2 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 7.98 (d, J=2.6 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 6.33 (t, J=7.3 Hz, 1H), 5.94 (d, J=7.3 Hz, 1H), 4.59 (s, 2H), 2.69 (br s, 6H), 2.38 (s, 3H). MS (ES+): 445.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30]([N:35]=[C:36]=[O:37])=[CH:29][C:28]=2[O:27]1.C(Cl)Cl.CO>C(#N)C>[O:34]1[C:33]2[CH:32]=[CH:31][C:30]([NH:35][C:36]([NH:1][C:2]3[C:15]4[C:6](=[CH:7][C:8]5[C:9]6[C:14]=4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:11](=[O:22])[C:10]=6[CH:23]=[CH:24][CH:25]=5)[CH:5]=[CH:4][CH:3]=3)=[O:37])=[CH:29][C:28]=2[O:27][CH2:26]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)Nc5ccc6c(c5)OCO6)c4c(c23)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 4 mL of acetonitrile was stirred at 20° C. 3,4-(methylenedioxy)phenyl isocyanate (2 molar equivalents) in 3 mL acetonitrile were added. The mixture was magnetically stirred at 20° C. during 18 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 volume ratio) to provide 125 mg (yield: 84%) of the desired product (formula below) as an orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:17][CH:18]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1ccc(NC(=O)[C@H](COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)[C@H](COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (200 mg), ethanol (5 ml), and 2N NaOH (2 ml) was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove ethanol completely that a small amount of purified water was added to the residue, and the whole was concentrated under reduced pressure. The residue was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated saline solution and dried over Na2SO4. The solvent was evaporated under reduced pressure to obtain (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (147 mg).
Reaction SMILES: NC(C1C=CC(Cl)=CC=1)(C)C(O)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH3:27])[CH2:25][O:24][C:23]([NH2:26])=[N:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@@:21]2([CH3:27])[CH2:25][O:24][C:23]([NH2:26])=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC1(c2ccc(Cl)cc2)COC(N)=N1
Agent: CC(N)(C(=O)O)c1ccc(Cl)cc1
Product: C[C@]1(c2ccc(Cl)cc2)COC(N)=N1

Procedure:
In analogy to example 126 (RS)-2-amino-2-(4-chloro-phenyl)-propionic acid was converted to (RS)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine which was subsequently separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. Off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].Cl>O.C(O)C>[CH2:13]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCOc1ccc(C(=O)O)c(Cl)c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A mixture of 4.0 parts of 2-chloro-4-hydroxybenzoic acid, 8.3 parts of 1-bromoheptane, 2.6 parts of potassium hydroxide, 10 parts of water and 90 parts by volume of ethanol was refluxed for 20 hours. A solution of 2.5 parts of potassium hydroxide in 50 parts of water was then added and refluxing continued for an additional 1.5 hours. The reaction mixture was diluted with 100 parts of water, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The combined extracts were dried over sodium sulfate, the solvent evaporated and the resultant residue recrystallized from hexane. 4.5 Parts of 4-heptyloxy-2-chlorobenzoic acid (75% yield) was obtained having a melting point of 76°-78° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=2[CH2:11]O)[CH2:3][CH2:2]1.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH2:11][C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: OCc1c(F)cccc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1cccc(C2CC2)c1CCl
Yield: 54.1 %

Procedure:
(2-Cyclopropyl-6-fluorophenyl)-methanol (4, 5.56 g, 34 mmol) was dissolved in dichloromethane (100 mL) and thionyl chloride (2.49 mL, 34 mmol) was added. The mixture was refluxed for 4 h and evaporated. The crude product was purified by column chromatography over silica, eluting with n-hexane:ethyl acetate (95:5). The title compound (3.41 g, 18.4 mmol, 54%) was isolated as a pale yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:25])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([Cl:23])[CH:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)[CH3:11])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[Cl:24][C:14]1[CH:13]=[C:12]([CH:10]([CH3:11])[C:9]([OH:25])=[O:8])[CH:17]=[CH:16][C:15]=1[N:18]1[CH:22]=[C:21]([Cl:23])[CH:20]=[N:19]1
Reactant: CC(C(=O)OCc1ccccc1)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 80.7 %

Procedure:
375 mg (1 mmole) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid benzyl ester are hydrogenolyzed in the presence of 50 mg of 10% palladium/activated charcoal at room temperature and at atmospheric pressure in a mixture of 100 ml of ethyl acetate and 10 ml of glacial acetic acid in a rotary hydrogenation apparatus until the theoretical amount of hydrogen has been absorbed. Filtration from the catalyst is effected, the filtrate is concentrated in a vacuum, and the residue is dissolved in a 1 N solution of sodium hydroxide. The resulting aqueous solution is extracted with benzene; acidification is effected with 1 N hydrochloric acid, followed by extraction again with benzene. The organic phase is dried and concentrated to yield 230 mg (80.7% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid (m.p. 102° to 103° C.).
Reaction SMILES: [C:1]([C:3]1[C:4](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[O:5][C:6]([CH3:16])([CH3:15])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O>[N:22]([C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:6]([CH3:16])([CH3:15])[O:5][C:4](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:3]=2[C:1]#[N:2])=[CH:9][CH:10]=1)=[N+:23]=[N-:24]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a 200-mL round bottom flask with stirbar was added 2-[3-cyano-4-(4-fluoro-phenyl)-5,5-dimethyl-5H-furan-2-ylidene]-malononitrile (0.20 g, 0.716 mmol) and DMSO (8 mL). The mixture was stirred at room temperature, then sodium azide (0.08 g, 1.23 mind) was added to it and the reaction continued to react at room temperature. After 2 h, the reaction mixture was completely homogeneous. The product mixture was poured into ice-water (300 mL) and stirred 0.5 h. The yellow precipitate was filtered out through suction filtration. The solid was recrystallized from 1-propanol to give the final product as a yellow solid having a UV spectra as set forth in FIG. 25; (0.19 g, 88% yield), IR (neat): 2924, 2228, 2113, 1567, 1533, 1366, 1279, 1188, 1111, 841 cm−1. 1H NMR (400 MHz, DMSO): δ 7.94 (ddd, J=9.2, 2.8, 2.0 Hz, 2H), 7.40 (ddd, J=9.2, 2.8, 2.0 Hz, 2H), 1.78 (s, 6H), 13C NMR (100 MHz, DMSO): δ 177.1, 176.6, 145.0, 130.6, 123.4, 120.3, 112.3, 111.4, 111.3, 101.6, 100.3, 55.2, 24.9. UV-Vis (CH2Cl2): λmax=384 nm, ε=2.9×104 L·mol−1·cm−1.