Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(N)nc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (example 292) (185 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (113 mg, 63%). MS (ISP) 360.0 [(M+H)+]; mp 244–246° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 100 %

Procedure:
A mixture of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]dec-7-ene (36.7 mmole) and platinum oxide (0.15 g) was hydrogenated in ethanol for 1.5 hr. The catalyst was removed by filtration and the ethanol removed in vacuo to give the product (100%, mp: 51°-53° C.). Calc'd for C14H17FO2 : C, 71.17%; H, 7.26%. Found: C, 71.16%; H, 7.35%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:18]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[C:15]([CH3:28])[N:14]=1>>[CH3:12][C:13]1[C:18]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[C:15]([CH3:28])[N:14]=1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)c(C)n1
Reactant: Nc1ccc2cccnc2c1
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)c(C)n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared as the corresponding hydrochloride salt from 7-aminoquinoline (D55) (25 mg, 0.17 mmol) and 4-(2,6-dimethyl-3-pyridyl)benzoic acid (D56) (21 mg, 0.09 mmol) as a brown solid. 1H NMR (250 MHz, DMSO) δ (ppm): 9.15 (d, 1H), 9.01 (s, 1H), 8.94 (d, 1H), 8.28 (m, 5H), 7.84 (m, 2H), 7.72 (d, 2H), 2.79 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C[N:17]1CCOCC1.ClC(OCC(C)C)=O.[NH:31](N)[C@H:32]([C:34]([NH:36][C@H:37]([C:42]([N:44]([CH3:47])[O:45][CH3:46])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH3:33].Cl>C1COCC1.O1CCOCC1>[CH3:47][N:44]([C:42](=[O:43])[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:36][C:34](=[O:35])[C@H:32]([CH3:33])[NH:31][C:6](=[O:8])[C@H:2]([CH:3]([CH3:4])[CH3:5])[N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[NH2:17])[O:45][CH3:46]
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NN
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N(N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Boc-Val-OH (46 mmol) and N-methyl morpholine (46 mmol) in THF (20 ml) was added to a pre cooled solution of isobutyl chloroformate (46 mmol) in THF (30 ml) under nitrogen at between -10 and -15° C. over 30 minutes. The reaction was stirred at -10° C. for 1 hour after which time a solution of N-methyl morpholine (46 mmol) and HCl.H2N-Ala-Leu-N(OMe)Me (41.8 mmol) in 1,4-dioxane (30 ml) was added drop wise slowly. The reaction was left for 1 hour at -10° C. and then allowed to warm up to room temperature. After concentrating the solution under high vacuum, water (50 ml) and ethylacetate (200 ml) was added. The organic layer was then washed with 0.1 M citric acid solution (3×50 ml), then saturated sodium bicarbonate (3×50 ml), dried over magnesium sulphate and then concentrated under vacuum to give the product.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[N:17]1[CH:16]=[CH:15][C:14]([CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:20])=[O:2])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(OCc2ccncc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2ccncc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester (0.28 g, 1.03 mmol) in THF (5 ml) and MeOH (5 ml) at room temperature is added 2 N LiOH (0.52 ml, 1.032 mmol) and the resulting solution is stirred overnight. Further 2 N LiOH (0.103 ml) is added and the reaction mixture stirred for a further 1 hour. The reaction mixture is concentrated in vacuo and the residue is diluted with water (50 ml) followed by EtOAc. The aqueous phase is acidified to pH2 with 1 N HCl, and extracted with DCM. The organic phase is concentrated to a third of its volume in vacuo until a white powder precipitates which is collected by filtration to yield the title compound; [M+H]+ 258.0
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N([CH2:18][CH3:19])CC)C.[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])(=[O:22])[CH3:21].Cl>O1CCCC1>[C:20]([O:23][C:19]1[CH:18]=[CH:31][CH:32]=[CH:24][C:25]=1[C:26]([NH:1][C:2]1[CH:11]=[C:10]([NH:12][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][C:20](=[O:22])[CH3:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:27])(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(N)cc1N
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)=O)cc1NC(=O)c1ccccc1OC(C)=O
Reaction time: 2 h

Procedure:
A mixture of 6.64 g of methyl 2,4-diaminobenzoate, 11.5 ml of triethylamine and 50 ml of tetrahydrofuran was added dropwise to a solution of 17.4 g of 2-acetoxybenzoylchloride in 300 ml of tetrahydrofuran over 0.5 - 1 hour, while stirring at 5° - 10°C. The stirring was then continued at room temperature for 2 hours. The resulting reaction mixture was poured into 1.5 l of diluted hydrochloric acid to precipitate crystals. The crystals were recovered by filtration, washed with water, dried and recrystallized from ethyl acetate to yield 15 g of methyl 2,4-bis(2'-acetoxybenzamido)-benzoate having a melting point between 143° - 145°C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3ccc(C(F)(F)F)cc23)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a solution of 5-(5-(6-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 11 (93 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added at 0° C. triethylamine (37 μL, 0.26 mmol), methanesulfonyl chloride (20.5 μL, 0.26 mmol). The solution was stirred at RT for 1.5 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 16 was obtained (100 mg, 90.5% yield) as a pale yellow oil.
Reaction SMILES: [NH:1]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16][CH2:17][O:18][C:19]([CH3:21])=[O:20].[CH3:22][CH2:23][CH2:24]CCCC>C(Cl)Cl.[Pd]>[CH2:9]([N:1]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:23]([CH3:24])/[CH:22]=[CH:21]/[C:19]([O:18][CH2:17][CH3:16])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(C)=O
Reactant: CCCCCCC
Agent: [Pd]
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(C)N(Cc1ccccc1)Cc1ccccc1
Yield: 70 %

Procedure:
Reaction of 30 (rac-Ethyl (2E)-4-(chloroacetoxy)pent-2-enoate) (221 mg, 1.0 mmol) with Bn2NH (383 μL, 2.0 mmol) and 8 mol % [Pd] in CH2Cl2 (10 ml) at room temperature according to Example 2. Flash chromatography (AcOEt heptane fraction 5:95) yields 12 (rac-Ethyl (2E)-N,N-dibenzyl-4-aminopent-2-enoate) (227 mg, 70%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)c(I)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 4-bromo-2-iodophenol (5.00 g, 16.7 mmol), bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to the provide title compound (5.84 g, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.O>[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.O1CCCC1>[Si:17]([O:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C(O)Cc1ccc(CO)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CC(=O)O)s1
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a solution of 2-[5-(hydroxymethyl)-2-thienyl]acetic acid (500 mg, 2.91 mmol) and imidazole (415 mg, 6.11 mmol) was added tert-butyldimethylsilyl chloride (916 mg, 6.11 mmol) portionwise over 20 minutes. The resultant solution was stirred at room temperature for one hour, tetrahydrofuran (10 mL) was then added and the reaction mixture cooled in an ice-bath. A solution of potassium carbonate (500 mg, 3.62 mmol) in water (10 mL) was added and the reaction mixture stirred for 20 minutes. The reaction solution was diluted with ethyl acetate (30 mL) and washed with brine (2×30 mL). The organic phase was dried over magnesium sulfate, filtered and concentration in vacuo. The residue was purified by silica gel chromatography, eluting with 0-50% ethyl acetate in iso-hexane to give the title compound as a yellow oil (200 mg, 24%) which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1CCO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([OH:11])=[O:10])[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccccc1N1CCOCC1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1N1CCOCC1

Procedure:
Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 53:7557, (1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157° C. A 1.8 g sample of this compound in 5 ml of CH2Cl2 (chilled) was added a solution of 7.9 ml of oxalyl chloride in CH2Cl2 (2M) followed by the addition of 0.058 ml of N,N-dimethylformamide. The solution was stirred at room temperature for 6 hrs and the solvent removed. Toluene was added (2 times) and removed to give 2-(4-morpholino)benzoyl chloride as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O[CH:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15](O)=[O:16].[OH:22][N:23]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[OH:22][N:23]=[C:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:16]
Reactant: O=C1CCC(=O)N1O
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CC(C)CC(O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)C(CC(C)C)=NO)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30 Milliliters of water and 7.0 g of sodium hydrogen carbonate were added to a suspension of 17.5 g of diethyl aminomalonate hydrochloride in 150 ml of dichloromethane. After 20 minutes, the dichloromethane layer was separated and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain colorless oily diethyl aminomalonate. The diethyl aminomalonate was made into a solution of the diethyl aminomalonate, 10.0 g of α-hydroxyisocaproic acid and 8.7 g of N-hydroxysuccinimide dissolved in 200 ml of dioxane. To the solution was added 15.7 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred for 16 hours at room temperature and then filtered. The filtrate was subjected to removal of the solvent by evaporation. The residue was mixed with ethyl acetate, and the mixture was washed with 10% hydrochloric acid, water, an aqueous solution saturated with sodium hydrogen carbonate, and an aqueous solution saturated with NaCl solution in this order, and dried over magnesium sulfate. The solvent was removed by evaporation to obtain 29.19 g of diethyl N-(2-hydroxyimino- 4-methylpentanoyl)aminomalonate (Compound B-25) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][C@@H:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])[C:33]([N:21]2[CH2:22][CH2:23][N:18]([C:10]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:14][N:13]=[C:12]4[NH:15][CH:16]=[CH:17][C:11]=34)[CH2:19][CH2:20]2)=[O:34])=[CH:38][CH:39]=1
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)c1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
5-(3-Methoxyphenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.045 g, 0.118 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0425 g, 0.142 mmol) were placed in DCM (3 mL). HOBT-H2O (0.0253 g, 0.165 mmol), EDCI (0.0294 g, 0.153 mmol), and DIEA (d 0.742; 0.103 mL, 0.591 mmol) were then added, and the reaction was stirred for 2 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The product was dried, filtered, and concentrated to give the crude product. The crude product was purified (500:5 DCM:MeOH) to yield (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.038 g, 54.6% yield).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14](=[O:26])[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12][CH:11]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:11]1[CH:12]=[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14](=[O:26])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[C:10]=1[CH3:9]
Reactant: CCOC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 82.8 %

Procedure:
N-Iodosuccinimide (6.89 g, 30.6 mmol) was added to a solution of ethyl 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (9.9 g, 30.5 mmol) in DCM (45 ml) and TFA (38 ml) under a nitrogen atmosphere. After 19 h stirring at ambient temperature the solvent was concentrated in vacuo. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue to neutralize the remaining TFA. The organic phase was collected, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with DCM/methanol (10:0.2) to give the title compound as a yellow solid (11.4 g, 83%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:29][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:15][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(-c3ccccc3)noc2c1O
Yield: 61 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (1.0 g, 3.52 mmol), NBS (0.94 g, 5.28 mmol), and benzoyl peroxide (85 mg, 0.352 mmol) were added to 30 mL of carbon tetrachloride and refluxed for 16 h. Silica gel (10 g) was added and the solvent was evaporated. The crude was purified by flash chromatography (0-40% EtOAc/hexanes) to give 780 mg of the title compound. MS: (+) m/z 363.26, 365.17 (M+1, 79Br/81Br).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=2[F:44])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)c(F)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2ccc(C#N)cc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (3.25 g, 20.24 mmol) and 18-crown-6 (0.535 g, 2.024 mmol) in DMSO (40 ml) was added potassium tert-butoxide (20 wt % in THF) (12.49 g, 22.26 mmol) and the reaction mixture was stirred at rt for 30 minutes. Next, 4-bromo-3-fluorobenzonitrile (4.05 g, 20.24 mmol) was added and the reaction mixture stirred at 135° C. for 3 days. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (4.56 g, 16.30 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (dd, 1H), 7.59 (d, 1H), 7.35-7.43 (m, 1H), 7.30 (t, 1H), 6.89 (t, 1H), 2.24 (d, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:3]1[CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+]>C(O)C>[OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:3]1[CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(O)CCC1C(CCCCCCC(=O)OCC)CC(O)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)CCC1C(CCCCCCC(=O)O)CC(O)C1O
Yield: 45.6 %

Procedure:
Ethyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate (2.6 g.) [prepared as described in (p) above], ethanol (50 ml.) and 2N aqueous sodium hydroxide solution (50 ml.) were heated together at reflux for 18 hours. The ethanol was removed in vacuo, water (25 ml.) was added and the mixture was washed with diethyl ether. The aqueous phase { which has a solution of sodium 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate} was acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid, extracted with diethyl ether, and the ethereal extract dried over magnesium sulphate and evaporated in vacuo to give 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoic acid (1.1 g.).
Reaction SMILES: [CH2:1](I)[CH3:2].[Li]C(C)(C)C.CCCCC.[C:14]([N:33]1[CH:37]=[C:36]([CH:38]=[O:39])[N:35]=[CH:34]1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CCOCC.C1COCC1>[C:14]([N:33]1[CH:37]=[C:36]([CH:38]([OH:39])[CH2:1][CH3:2])[N:35]=[CH:34]1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCI
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.6 %

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, ethyl iodide (1.1 ml, 0.0136 mol) is dissolved in Et2O (25 ml). At −70° C., a 1.5 M solution of t-BuLi in pentane (17 ml, 0.026 mol) is added dropwise. The mixture is stirred 0.3 h at this temperature and 0.75 h at room temperature. A solution of 1-trityl-1H-imidazole-4-carbaldehyde x43 (2 g, 0.00591 mole) in THF (25 ml) is added dropwise at 0° C. The mixture is stirred for 1 h and poured onto ice. HCl is added until the pH is slightly acid (pH: 3-5) and the aqueous phase is extracted twice with Et2O. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 95/4.5/0.5 (v/v/v)) to afford 1.21 g of 1-(1-trityl-1H-imidazol-4-yl)propan-1-ol x88.