Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:31])[CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=45)[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:31][CH3:34])[CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=45)[S:18]3(=[O:29])=[O:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CN1CCN(c2ccc(F)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.41 g) in dimethylformamide (50 cc) is poured over 30 minutes into a mixture of sodium hydride (0.53 g) in a 50% dispersion in vaseline oil, and dimethylformamide (10 cc), under a current of argon, maintaining the temperature between 20 and 30° C. The reaction medium is stirred for 1 hour at a temperature of about 20° C. and then methyl iodide (0.7 cc) is added over 10 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The mixture is redissolved in distilled water (200 cc) and the organic phase is extracted with dichloromethane (4×100 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (10 cc). 2-(3-[4-(4-Fluoro phenyl)-1-p-iperazinyl]-2-methoxypropyl}naphtho[1,8cd]isothiazole 1,1-dioxide (2.1 g) is obtained, m.p. 128° C.
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]([O:25][CH2:26]C)=[O:24])[C:18]([O:20][CH2:21]C)=[O:19])=[CH:13][CH:12]=1)C1C=CC=CC=1>CO.[Pd]>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]([O:25][CH3:26])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)c1ccc(O)cc1

Procedure:
At room temperature and a hydrogen pressure of 5 bar, 94.3 g of diethyl (4-benzyloxyphenyl)malonate (J. Org. Chem. 46, 3007 (1981)) in 500 ml of methanol were hydrogenated in the presence of 5 g of palladium/carbon catalyst (5%). The catalyst was filtered off and the mixture was concentrated, to give the title product as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:16]>C(O)C.C(O)(C)C.O=[Pt]=O>[ClH:16].[CH:9]1([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1O
Reactant: O=C1CCCCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: Oc1ccccc1NC1CCCCC1

Procedure:
A mixture of 10.9 g (0.1 mol) of 2-aminophenol and 10.4 g (0.1 mol) of cyclohexanone in 200 ml of ethanol is hydrogenated over 0.2 g of PtO2 under standard conditions, 0.1 mol of HCl in isopropanol is added to the reaction mixture, the catalyst is filtered off and the filtrate is evaporated in vacuo and the residue is precipitated with ether.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.[C:12]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2c(c1)OCCO2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.600 g; 17.10 mmol), and K2CO3 (2.598 g; 18.80 mmol) in anh. acetone (40 ml) was stirred at rt, under nitrogen, for 1 h. Iodomethane (13.340 g; 94.00 mmol) was then added, and the resulting mixture was heated at reflux, under nitrogen, for 2 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the filtrate was concentrated to dryness under reduced pressure. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine as a yellow oil. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 167.11 g/mol.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:33])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCCCC=1>[Pd].C(O)C>[CH:1]1([NH:7][C:8](=[O:33])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NC1CCCCC1
Yield: 99.2 %

Procedure:
A mixture of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine cyclohexylamide (0.68 g) obtained in Example 4, palladium black (0.10 g), cyclohexene (4 ml), and ethanol (20 ml) was allowed to react under reflux of ethanol for one hour, while stirring. After cooling, the solid was filtered off and the filtrate was concentrated under reduced pressure to obtain N-(t-butyloxycarbonyl-4-hydroxy-L-phenylalanine cyclohexylamide (I) (0.54 g). The compound (I) (0.54 g) was dissolved, without purification, in N,N-dimethylformamide (10 ml), followed by adding sodium hydride (0.06 g) thereto. The mixture was stirred at room temperature for 30 minutes. To this solution was added a solution of phenacyl bromide (0.30 g) in N,N-dimethylformamide (5 ml). The reaction was carried out at room temperature for 4 hours, followed by adding ice-water thereto. The resultant oily product was extracted with ethyl acetate. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide (II) (0.61 g) was obtained. From the compound (II), N-(trans-4-aminomethylcyclohexylcarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide hydrochloride (0.38 g) was obtained, following the procedure of Example 7.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH2:33][C@@H:34]([OH:45])[CH2:35][NH:36][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[O:38])=[CH:28][C:27]=2[Cl:46])[C:21]1=[O:47])([C:14]([CH3:17])([CH3:16])[CH3:15])([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:48](N1C=CN=C1)(N1C=CN=C1)=[O:49]>C(#N)CCC.CN(C)C1C=CN=CC=1>[Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][C@H:34]([CH2:35][NH:36][C:37]([C:39]4[S:40][C:41]([Cl:44])=[CH:42][CH:43]=4)=[O:38])[O:45][C:48]3=[O:49])=[CH:28][C:27]=2[Cl:46])[C:21]1=[O:47])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCC1CCCN(c2ccc(NC[C@@H](O)CNC(=O)c3ccc(Cl)s3)cc2Cl)C1=O)(c1ccccc1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: CCCC#N
Product: CC(C)(C)[Si](OCC1CCCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2Cl)C1=O)(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
A solution of 850 mg (1.196 mmol) of the compound from example 94A and 387 mg (2.39 mmol) of carbonyldiimidazole in 30 ml of butyronitrile is admixed with 3 mg (0.024 mmol) of 4-dimethylaminopyridine and heated to reflux. After 15 hours, the majority of the solvent is removed on a rotary evaporator. The product is isolated further by means of preparative HPLC with an acetonitrile/water mixture. This affords 605 mg (69% of theory) of the title compound.
Reaction SMILES: C(O)(=O)C.N1C=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:15]=[C:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=3)[N:26]=2)[CH:13]=1.COC1CCC(OC)O1>O>[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[N:15]=[C:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([CH2:36][N:37]4[CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:34][CH:35]=3)[N:26]=2)[CH:13]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN)cc4)no3)cc2C)cc1
Reactant: c1ccncc1
Agent: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(Cn5cccc5)cc4)no3)cc2C)cc1
Temperature: 100 °C
Yield: 32.4 %

Procedure:
To a solution of acetic acid (348 μL, 6.08 mmol) in water (194 μL) were added successively pyridine (491 μL, 6.08 mmol), 1-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanamine (Example 139, 130 mg, 0.362 mmol) and 2,5-dimethoxytetrahydrofuran (47 μL, 0.362 mmol). The reaction mixture was heated to 100° C. for 20 h. After being cooled to rt, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude product was first subjected to MPLC (silica, cyclohexane/ethyl acetate 4:1) and then to preparative HPLC affording the title compound as a white solid (48 mg, 31%): NMR (400 MHz, DMSO-d6) 8.02 (d, 2H), 7.35 (d, 2H), 7.18 (d, 2H), 7.11 (d, 2H), 6.91 (s, 1H), 6.86 (t, 2H), 6.05 (t, 2H), 5.42 (s, 2H), 5.21 (s, 2H), 2.32 (s, 3H), 2.27 (s, 3H); ES-MS m/z 410, HPLC RT (Method K) 1.54 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]1[O:4][CH2:3]1.[OH2:11]>C(O)(=O)CCCCCCCCCCC.[OH-].[K+]>[CH2:1]([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]([CH2:3][OH:11])[OH:4]
Reactant: O
Reactant: CC(C)CCOCC1CO1
Agent: CCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CC(C)CCOCC(O)CO
Temperature: 157 °C
Yield: 99.7 %

Procedure:
The crude isoamyl glycidyl ether (140 g), water (140 g; 7.78 mol), lauric acid (7.64 g; 0.038 mol) and potassium hydroxide (2.14 g; 0.038 mol) were placed in a 2-l autoclave, and the mixture was heated up to 157° C. while stirring it. The mixture was stirred for 5 hours as it was, and was then allowed to cool down to room temperature. The mixture was extracted with ethyl acetate (500 ml), and the extract was washed twice with water (300 ml). The solvent was then distilled off to obtain 157 g of crude monoisoamyl glyceryl ether. This crude product was purified by vacuum distillation (2 mmHg, 114-115° C.) to obtain 103 g of monoisoamyl glyceryl ether as a colorless transparent oil (total yield: 71%). Quenching of a proton signal (methylene in an epoxy ring) at δ=2.60, 2.80 was observed by 1H-NMR (200 MHz), thereby identifying the compound. The purity of the compound was found to be at least 99% by GLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
2-Chloro-4-fluorophenol (5.64 g, 38.5 mmol) was added to a solution of acetic acid (16.5 mL), nitric acid (8.66 mL) and water (7.5 mL) at 0° C. The reaction mixture was stirred vigorously for 5 hours at 0° C. The resulting precipitate was filtered, washed with water and dried under vacuum to yield 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol, 83%) as a yellow powder.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH2:12])=[O:11])=[N:6][C:5]=12.CO[C:15](OC)([N:17]([CH3:19])[CH3:18])[CH3:16]>>[CH3:18][N:17]([C:15](=[N:12][C:10]([C:7]1[CH:8]=[CH:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[N:6]=1)=[O:11])[CH3:16])[CH3:19]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1ccn2ccnc2n1
Product: CC(=NC(=O)c1ccn2ccnc2n1)N(C)C
Temperature: 25 °C

Procedure:
A mixture of imidazo[1,2-α]pyrimidine-7-carboxylic acid amide (310 mg) and N,N-dimethylacetamide dimethylacetal (270 mg) was heated at reflux for 16 h then cooled to ambient temperature. The reaction was then partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give imidazo[1,2-α]pyrimidine-7-carboxylic acid [1-(N,N-dimethylamino)ethylidene]amide as a brown oil. This oil was dissolved in 70% aqueous acetic acid (120 ml) and 1,4-dioxane (60 ml). A solution of hydroxylamine in water (40 wt. %, 0.15 ml) was then added and the mixture heated at 100° C. for 2 h then cooled to ambient temperature. This reaction mixture was dissolved in 50% methanol in dichloromethane and pre-adsorbed onto silica. Purification on silica gel eluting with dichloromethane (+1% conc. ammonia) on a gradient of methanol (2-5%) gave 7-(3-methyl-[1,2,4]oxadiazol-5-yl)imidazo[1,2-α]pyrimidine as a yellow solid (110 mg, 29% over 2 steps): δH (360 MHz, DMSO) 2.43 (3H, s), 7.76 (1H, d, J 7), 8.02 (1H, d, J 1), 8.19 (1H, d, J 1), 9.22 (1H, d, J 7).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[O:17])[O:15][C:14]([CH3:19])([CH3:18])[O:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.[CH:23]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[O:17])[O:15][C:14]([CH3:19])([CH3:18])[O:13][C:12]=3[CH:20]=2)[C:30](=[O:31])[CH2:29][CH2:28][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)c2ccc(NCc3ccc(Br)cc3)cc2O1
Reactant: O=C(Cl)CCC1CCCC1
Product: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1

Procedure:
The titled compound was prepared following the procedure M using 7-[(4-bromobenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropionyl chloride as a white powder (86%). M+ (ESI): 488.0. HPLC, Rt: 5.41 min (Purity: 99.9%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42].CN(C)CCN>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:18]([NH:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)CNC(=O)[C@H](N)CCSC
Agent: CC(C)COC(=O)Cl
Agent: CN(C)CCN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16.88 g of Boc-L-tyrosine in 50 ml of dry dimethylformamide is added 6.65 ml of N-methylmorpholine. The reaction mixture is cooled to -40° C. and 7.84 ml of isobutylchloroformate is added. The reaction mixture is allowed to warm to 0° C. over a 15 minute period then 13.32 g of methyl D-methionyl-glycinate hydrochloride dissolved in 50 ml of dimethylformamide is added followed immediately by 5.2 ml of N-methylmorpholine. The reaction mixture is stirred for 30 minutes at 0° C. After storage overnight at 5° C., 3 ml of N,N-dimethylethylenediamine is added and the reaction mixture is stirred for 15 minutes at room temperature. The solvent is removed under vacuum at 35° C. and 1 mm of pressure and oily residue is dissolved in a mixture of 100 ml of water and 700 ml of ethyl acetate. The ethyl acetate layer is separated and washed three times with 80 ml of a 0.5 M solution of potassium bisulfate, 2 times with 80 ml of water, 2 times with 80 ml of a 0.5 solution of potassium carbonate, and 3 times with 100 ml of a 10% solution of sodium sulfate then dried over magnesium sulfate. The solvent is removed under pressure. The residue is dissolved in 1.2 liters of 5% ethyl acetate in chloroform and purified by low pressure chromatography on silica gel then reduced to dryness under reduced pressure and recrystallized from ethyl acetate to give methyl Boc-L-tyrosyl-D-methionyl-glycinate which is represented by the following formula
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C(N(CC)CC)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:13])([F:25])[F:24]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)c1c(O)c2ccccc2oc1=O

Procedure:
According to the procedure of example 17, 4-hydroxycoumarin (2.00 g. 12.8 mmol) and 2-trifluoromethylphenylisocyanate(1.93 ml, 12.8 mmol) were reacted in the presence of triethylamine (0.05 ml) to generate the title compound as an off-white solid, mp 157-159° C., (2.2 g, 6.30 mmol, 49.3%). Analysis: Calculated for C17H10NO4F3 : C, 58.45; H, 2.86; N, 4.01. Found: C, 58.47; H, 3.04; N, 4.02. 1H NMR (CDCl3): 8.06 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.38 (m, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=[O:5])C.C(OC(=O)C(CC)CCN1C(=S)N2C3C=C(C4C=CC(Cl)=CC=4)OC=3C=C2C1=O)C.[CH2:51]([O:53][P:54]([CH2:59][CH2:60][CH2:61][N:62]=[C:63]=[S:64])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52].C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:51]([O:53][P:54]([CH2:59][CH2:60][CH2:61][N:62]1[C:63](=[S:64])[N:10]2[C:9]3[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)[O:13][C:8]=3[CH:7]=[C:6]2[C:4]1=[O:5])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]
Reactant: CCOP(=O)(CCCN=C=S)OCC
Reactant: CCOC(=O)c1cc2oc(-c3ccc(Cl)cc3)cc2[nH]1
Agent: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOP(=O)(CCCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S)OCC
Temperature: 110 °C
Yield: 59.4 %

Procedure:
2-(4-Chloro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (60.97 mg, 0.21 mmol), prepared by the procedure described above (see, Compound 4), (3-isothiocyanopropyl)phosphonic acid diethyl ester (500 mg, 2.1 mmol) and a fine powder of anhydrous K2CO3 (27.6 mg, 0.2 mmol) were mixed together in a sealed tube, provided with a magnetic stirrer, and the mixture was heated at 110° C. for 2 hours. The mixture was then cooled to room temperature, ethanol (2 ml) was added, and the formed precipitate was filtered. The compound was recrystallized from ethanol to give of Compound 27 (60 mg, 60% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:30]([C:29]4[CH:28]=[CH:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)=[CH:34][CH:33]=4)=[O:31])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)ccc3o2)C1
Reaction time: 72 h
Yield: 77.2 %

Procedure:
Combine 2-(3-dimethylamino-pyrrolidin-1-yl)-benzooxazol-5-ylamine (0.100 g, 0.406 mmol), 4-(4-fluorophenyl)benzoic acid (0.073 g, 0.338 mmol), and HATU (0.129 g, 0.338 mmol) in CH2Cl2 and add DIEA (0.18 mL, 1.01 mmol). Shake the mixture in a shaker block at 40° C. for 72 h. Dilute the reaction mixture with CH2Cl2 (30 mL), and wash with saturated NaHCO3 (aqueous) (2×25 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate in vacuo. Subject the crude product to flash column chromatography (40 g column) eluting with 8% MeOH/CH2Cl2, to yield the title compound as a bluish-white solid (0.116 g, 65%). mass spectrum (m/e): 445.3 [M+1], 443.3 [M−1]. 1H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.85-7.79 (m, 4H), 7.75 (d, 1H, J=2.2 Hz), 7.41-7.30 (m, 4H), 3.79 (dd, 1H, J=9.9, 7.1 Hz), 3.72 (m, 1H), 3.54 (m, 1H), 3.31 (m, 1H), 2.86 (m, 1H), 2.25-2.12 (m, 7H), 1.86 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Br)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 134A (465 mg) and 1-(3-bromopropoxy)naphthalene (431 mg) in N,N-dimethylformamide (10 ml) was added cesium carbonate (1059 mg). The reaction was stirred at room temperature overnight and diluted with ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by RPHPLC to provide ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-D6) δ 8.13 (d, J=7.98 Hz, 1H), 7.85 (d, J=7.67 Hz, 1H), 7.74 (dd, J=9.21, 4.30 Hz, 1H), 7.42-7.58 (m, 3H), 7.37 (t, J=7.98 Hz, 1H), 7.27 (dd, J=8.90, 2.45 Hz, 1H), 7.10-7.20 (m, 1H), 6.85 (d, J=7.36 Hz, 1H), 4.87 (t, J=6.90 Hz, 2H), 4.14 (t, J=5.83 Hz, 2H), 2.21-2.39 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([N:27]([CH3:26])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNCc1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid (50 mg, 0.14 mmol), N-methylbenzylamine (0.022 mL, 0.17 mmol), iPr2NEt (0.07 mL, 0.50 mmol) in DMF (3 mL) was added HATU (68 mg, 0.18 mmol) and stirred at rt overnight. The reaction mixture was poured into ice-water, and the solid was collected by filtration. The solid was re-dissolved in CH2Cl2 and purified by preparative TLC (CH2Cl2-MeOH-Hexane, 8:2:2) affording the product as a light yellow powder. LC-MS: 467 (M++1). 1H NMR (CDCl3): δ 2.92 and 3.00 (each s, 3H), 3.05˜3.12 (m, 4H), 3.62˜3.72 (m, 4H), 4.12˜4.20 (m, 2H), 4.52 and 4.62 (each s, 2H), 5.08 (br.s, 2H), 5.94 (m, 1H), 6.15 (m, 1H), 7.14˜7.24 (m, 3H), 7.26˜7.40 (m, 3H), 7.58˜7.62 (m, 1H), 7.68˜7.72 (m, 1H).