Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[C:17]([C:20]1[CH:21]=[C:22](I)[CH:23]=[CH:24][CH:25]=1)([OH:19])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:17]([C:20]1[CH:21]=[CH:22][C:23]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:24][CH:25]=1)([OH:19])=[O:18]
Reactant: O=C(O)c1cccc(I)c1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.96 g (20 mmole) of meta-carboxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled till room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, and dissolved in aqueous alkali. Aqueous phase was separated and treated with aqueous HCl. White precipitated was isolated washed with cooled ethanol and dried under vacuum to obtain 2 g (43%) of 2-(4-carboxy-phenyl)-indene.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[S:22]1[C:26]2[C:27]([C:31]3[O:41][C:34]4=[C:35]([NH2:40])[N:36]=[CH:37][C:38](I)=[C:33]4[CH:32]=3)=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[S:22]1[C:26]2[C:27]([C:31]3[O:41][C:34]4=[C:35]([NH2:40])[N:36]=[CH:37][C:38]([C:11]5[CH:10]=[N:9][N:8]([CH:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[CH:12]=5)=[C:33]4[CH:32]=3)=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[CH:23]1
Reactant: Nc1ncc(I)c2cc(-c3cccc4ccsc34)oc12
Reactant: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6ccsc56)cc34)cn2)CC1
Yield: 33 %

Procedure:
A solution of 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (42.0 mg, 0.14 mmol) and 2-(1-benzothiophen-7-yl)-4-iodofuro[2,3-c]pyridin-7-amine (47.1 mg, 0.12 mmol) in 1,4-dioxane (0.81 mL) and H2O (0.2 mL) was charged with potassium carbonate (25 mg, 0.18 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (0.9 mg, 0.01 mmol) under an atmosphere of nitrogen. The mixture was irradiated in a Biotage microwave reactor at 100° C. for 100 min. The reaction mixture was concentrated in vacuo to a solid. Purification by flash chromatography (0 to 10% 7 N NH3/MeOH:EtOAc afforded 17 mg (33%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.11 (d, J=7.58 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J=8.08 Hz, 1H), 7.88 (d, J=7.07 Hz, 2H), 7.70 (d, J=5.31 Hz, 1H), 7.45-7.55 (m, 3H), 4.27 (dt, J=15.35, 7.86 Hz, 1H), 3.06 (d, J=11.62 Hz, 2H), 2.38 (s, 3H), 2.25-2.34 (m, 2H), 2.13-2.22 (m, 4H); MS (ESI): 431.17 [M+H]+; HPLC tR=0.90 min (TOF: polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3NC4C(=O)N(CCC)C(=O)N(CCC)C=4N=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].C(=O)([O-])[O-].[K+].[K+].C(Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH2:44]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:2][C:3]([C:5]12[CH2:6][CH2:7][C:8]([CH2:13][OH:44])([CH2:9][CH2:10]1)[CH2:11][CH2:12]2)=[O:4])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O
Reactant: BrCc1ccccc1
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C12CCC(CO)(CC1)CC2

Procedure:
4-Hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid (XVII, Example 14, 24.8 g 135 mmol) is dissolved in DMF (950 ml). Anhydrous potassium carbonate (25 g, 181 mmol) is added to the solution slowly. Benzyl bromide (22 g, 12.94 mmol) is then added. The reaction mixture is heated at 80° for 16 hr. To the reaction mixture is added water (150 ml) and concentrated to give an oil, which was dissolved in ethyl acetate/hexane (5/1, 500 ml). The mixture is washed with saline (2×200 ml), dried over anhydrous sodium sulfate and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 7.39, 5.11, 3.28, 1.84 and 1.41.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C[Si](C)(C)CC[O:28][C:29]([C:31]1([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:39]=2)[CH2:36][CH2:35][CH2:34][C:33](=[CH2:37])[CH2:32]1)=[O:30]>>[C:44]([C:40]1[CH:39]=[C:38]([C:31]2([C:29]([OH:30])=[O:28])[CH2:36][CH2:35][CH2:34][C:33](=[CH2:37])[CH2:32]2)[CH:43]=[CH:42][CH:41]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: C=C1CCCC(C(=O)OCC[Si](C)(C)C)(c2cccc(C(C)(C)C)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1CCCC(C(=O)O)(c2cccc(C(C)(C)C)c2)C1
Reaction time: 16 h
Yield: 107.2 %

Procedure:
A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (15.0 mL, 15.0 mmol) was added to 1-(3-tert-butyl-phenyl)-3-methylene-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester (2.67 mg, 7.16 mmol). After stirring for 16 h, the solution was concentrated, diluted with 10% aqueous hydrochloric acid, and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield 2.09 g (100% yield) of 1-(3-tert-butyl-phenyl)-3-methylene-cyclohexanecarboxylic acid as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19]([C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])=[CH:30][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1)=[O:20]
Reactant: CCNCC
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Product: CCN(CC)CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 147 for 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide and diethyl amine were reacted to give 169. MS: (ESI+) 498.2
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11](O)=O)=[CH:4][CH:3]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28]>P(=O)(O)(O)O>[NH:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:29]=[C:11]1[CH2:10][CH2:9][C:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: Nc1ccccc1N
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=P(O)(O)O
Product: CC(CCc1nc2ccccc2[nH]1)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a four neck 250 mL reaction kettle equipped with an overhead stirrer, thermocouple, gas inlets adapter and condenser, were charged 30.01 gram 4,4-bis(4-hydroxyphenyl)pentanoic acid (0.1048 moles), 15.17 gram 1,2-phenylenediamine (0.1403 moles) and 150 gram polyphosphoric acid. The mixture was stirred at 250 rpm at room temperature for 15 minutes and heated up to 120° C. under argon atmosphere. The reaction was continued for 3 hours and the product was cooled to room temperature. The product obtained in phosphoric acid solution was isolated by precipitating in water followed by neutralization and filtration. The isolated product was dried in vacuum at 90° C. for 48 hours. The conversion of acid to benzimidazole functionality was confirmed by IR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 31.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.14 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.525 g, 31.8%). 1H NMR δ(400 MHz, DMSO-d6) 9.96 (s, 1H), 8.91 (s, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.26 (dd, J=3.2, 9.3 Hz, 1H), 6.18 (s, 1H), 5.86 (m, 1H), 3.67 (m, 2H), 3.37 (m, 4H), 2.54 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.71 (m, 2H), 1.53 (m, 2H), 1.39 (s, 9H), 1.33 (s, 6H).
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH2:9][CH2:8]1)=[O:6].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:29]([BH3-])#[N:30].[Na+]>CO>[CH2:21]([N:30]([CH2:29][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:14]([Cl:20])=[CH:15][N:16]=[CH:17][C:18]=2[Cl:19])[CH2:11][CH2:12]1)=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: O=Cc1ccccc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NCCN(Cc1ccccc1)Cc1ccccc1)C1CCN(c2c(Cl)cncc2Cl)CC1
Reaction time: 0.75 h
Yield: 54 %

Procedure:
To a solution of N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E13 (20 mg, 0.060 mmol) in MeOH (2 mL) was added benzaldehyde (19 μL, 0.19 mmol). After stirring for 45 min, sodium cyanoborohydride (12 mg, 0.19 mmol) was added and the mixture was stirred for a further 16 h. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (20 mL), washed with a saturated solution of sodium hydrogencarbonate (25 mL), brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a white solid (14 mg, 54%), m.p. 147-149° C.; umax (CHCl3)/cm−1 3007, 2837, 1658, 1558, 1509, 1457, 1146; m/z (ESI) C27H31Cl2N4O requires 497.1869, found [M+H]+ 497.1872.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[C:25](Cl)[N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Cl>CC(N(C)C)=O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[C:25]([S:1][CH2:2][CH2:3][OH:4])[N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: OCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2SCCO)c1
Yield: 69.5 %

Procedure:
To a solution of 2-mercaptoethanol (1.31 g) in dimethylacetamide (15 ml) is added sodium hydride (62.3% dispersion-type, 520 mg) under argon atmosphere. Five minutes later, to the mixture is added 4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (1.5 g), and the mixture is reacted under argon atmosphere at 70° C. for two hours, at 100° C. for three hours, and further reacted at 130° C. for two hours. The reaction solution is treated with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=70:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-{6-(2-hydroxyethylthio)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (1.14 g) as crystals.
Reaction SMILES: [CH:1]1([S:7][C:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([OH:28])=[C:21]([O:26][CH3:27])[CH:22]=3)[CH2:17]2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:41][CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O>CC(=O)CC>[Cl:41][CH2:42][CH2:43][O:28][C:20]1[CH:19]=[C:18]2[C:23]([CH2:24][CH2:25][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([S:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C:9]#[N:10])[CH2:17]2)=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1cc2c(cc1O)CN(CCCCCC(C#N)(SC1CCCCC1)c1ccc(OC)c(OC)c1)CC2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OCCCl)cc3C2)SC2CCCCC2)cc1OC

Procedure:
A mixture, under argon, of 2.0 g of product from Example 114, 15 ml of 1N sodium hydroxide, 5.4 ml of 2-chloroethyl-p-toluene sulfonate and 70 ml of 2-butanone is heated at reflux temperature for 18 hours. The mixture is cooled, concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium chloride, dried, and concentrated in Vacuo to give an oil. The oil is purified by chromatography (silica gel: methylene chloride, 0.5%, 1.0% and 1.5% methyl alcohol/methylene chloride) to give 1.7 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([OH:19])=O)[N:9]=[C:10]([C:11]3[NH:12][CH:13]=[CH:14][N:15]=3)[C:3]=12.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][NH:31][C:30]=3[CH:29]=[N:28]2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([N:31]3[CH2:32][CH2:33][CH2:34][C:35]4[N:27]([C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)[N:28]=[CH:29][C:30]3=4)=[O:19])[N:9]=[C:10]([C:11]3[NH:15][CH:14]=[CH:13][N:12]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The compound was prepared from 2-(4-amino-3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine above using General Method A. The product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (6.4 mg). 1H NMR (400 MHz, MeOH-d4) δ 8.35 (s, 1H), 8.15 (s, 1H), 7.54 (m, 2H), 7.27 (m, 4H), 5.70 (s, 2H), 4.00 (m, 2H), 2.91 (t, J=6.2 Hz, 2H), 2.18 (m, 2H); MS: (ES) m/z calculated for C22H20FN10O [M+H]+ 459.18, found 459.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][CH2:12][CH2:11][Br:10]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(OCCCBr)c(Cl)c1
Reaction time: 0.19 h

Procedure:
2,4-Dichlorophenol (20.5 g, 0.126 mol), 1,3-dibromopropane (49.1 g, 0.243 mol) and a solution of 5 g NaOH in 20 ml H2O were refluxed for 75 min (oil bath 135°). A solution of 4.5 g of NaOH in 32 ml H2O was added and the mixture was heated on a steam bath for 11/2 hr. The layers were separated, the organic layer was extracted with water and then subjected to vacuum distillation (3-4 mm). A 19.6 g forecut was collected from room temperature to 50°. The product (20.5 g, 57%) distilled from 134°-137°. HPLC analysis (MeOH: 0.05N NH4HCO2 80:20) showed the material to be 87% pure. Retention times of the impurities were 4.8 and 8.8 min while the product was 11.6 min. Extraction with water had no effect on the composition. As the impurities were found to be inert during the subsequent reactions, the material was used without further purification.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3]([CH3:5])=O.[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10]>C(Cl)(Cl)Cl>[CH3:5][C:3]1([CH:2]([Cl:6])[Cl:1])[S:11][CH2:7][CH2:8][CH2:9][S:10]1
Reactant: CC(=O)C(Cl)Cl
Reactant: SCCCS
Solvent: ClC(Cl)Cl
Product: CC1(C(Cl)Cl)SCCCS1
Temperature: 0 °C
Yield: 80 %

Procedure:
In a three-necked flask equipped with a magnetic stirrer and having a nitrogen blanket at the inlet and outlet, are added 13.97 grams (0.11 mole) of 1,1-dichloroacetone, 10.8 grams (0.10 mole) of 1,3-propanedithiol and 50 milliliters of chloroform. The reaction mixture is cooled to 0° C. A slow steam of hydrogen chloride gas is then bubbled through the solution for approximately five minutes. Upon the reaction mixture reaching saturation, the mixture is allowed to set at room temperature for approximately thirty minutes. The solvent is then evaporated and a crude 2-methyl-2-dichloromethyl-1,3-dithiane derivative is expected in a yield of approximately 80-90%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([C:20]([O:22]C)=[O:21])[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1coc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCc2nc(C(=O)O)co2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a stirred solution of methyl 2-[[3-[(S)-(tert-butoxycarbonylamino)-phenyl-methyl]phenoxy]methyl]oxazole-4-carboxylate (0.8 g, 1.825 mmol) in THF (9.2 mL) and methanol (9.2 mL) was added a solution of lithium hydroxide monohydrate (153.1 mg, 3.65 mmol) in water (3.6 mL). The reaction was stirred at room temperature for 18 h. The majority of the solvent was removed in vacuo. The residue was diluted with water (50 mL) and cooled to 0° C. 2N aqueous HCl (1.82 mL) was added dropwise. The reaction mixture was extracted with ethyl acetate (3×20 mL) and the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a colourless solid (736 mg, 95%).
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14](C(=O)C(C)(C)C)[N:13]=[CH:12]4)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:2]2[CH2:3][CH:4]3[CH:7]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH:1]2[CH2:6][CH2:5]3)=[CH:27][CH:26]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3NC4)ccc21
Product: Cc1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1

Procedure:
Reaction of Intermediate 14 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: CCCCNC(=O)C(C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7.23 g of 3,4,5-trimethoxycinnamoyl chloride is added with stirring at room temperature to a solution of 5.00 g of 1-[1-(butylaminocarbonyl)ethyl]piperazine in 80 ml of chloroform, and the resulting solution is stirred at room temperature for 15 minutes.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH3:21])[CH:7]=1>CO>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:22])=[O:4])=[CH:7][C:8]=1[O:20][CH3:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Yield: 94.8 %

Procedure:
A solution of sodium hydroxide (2.0 g) in methanol (50 ml) was added to a solution of 4-benzyloxy-3-methoxy benzoic acid methyl ester (4.64 g) in methanol (50 ml) and refluxed for 4 hrs. After removal of methanol under reduced pressure the residue was dissolved in water (150 ml) and washed with ethyl acetate (2×50 ml). The aqueous layer was acidified with 2N hydrochloric acid to pH 2. The precipitated product was collected by filtration which on drying under vacuum provided 4.17 g of 4-benzyloxy-3-methoxy benzoic acid. (Yield=74%)
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C[O:34]CC1>>[CH2:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([OH:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1CCOC1
Reactant: BrCCCCCCCCCCOCc1ccccc1
Reactant: CCCCCCCCBr
Agent: II
Product: CCCCCCCCC(O)CCCCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Mg metal (0.65 g, 26.83 mmol) and a catalytic amount of Iodine in dry THF (20 ml) at 70° C., 1-bromooctane (3.57 ml, 23.48 mmol) in THF (10 ml) was added dropwise. Stirring was continued for another 30 minutes at this temperature, then the reaction mixture was cooled to room temperature, and was added slowly to a stirred solution of (((10-bromodecyl)oxy)methyl)benzene (4.4 g, 16.77 mmol) in THF (30 ml) at 0° C. The reaction was warmed to room temperature and stirring was continued for another 2 h. The reaction was quenched with ammonium chloride solution, extracted with EtOAc (3×50 ml), the combined organic layers were washed with brine solution, dried over MgSO4 and concentrated. The crude product was purified by silica gel column (12% EtOAc in Hexane) to give 18-(benzyloxy)octadecan-9-ol as a low melting white colored solid (3.85 g, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([CH:28]2[CH2:29][CH2:30]2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)C2CC2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 5, using the following starting materials: (3-{4-amino-2-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester and trimethylacetyl chloride.