Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[C:2](S(OC)(=O)=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:13][C:14](C)([O-:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[CH2:12]([O:16][CH:14]([CH3:15])[CH3:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[O-]
Reactant: COS(=O)(=O)c1ccccc1C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,3-diPEGoxy-2-benzyloxypropane [MW poly(ethylene glycol) (PEG)=9 kDa] (5.0 g, 0.55 mmoles) from Step A was placed in a two-necked round bottom flask and dissolved in 150 ml of toluene. The flask was fitted with a septum and a Dean-Stark trap and the compound was azeotropically dried under an inert atmosphere. The trap was replaced with a reflux condenser and the temperature of the flask was kept at 45° C. by placing the flask in a constant temperature oil bath. Methyl toluenesulfonate (1.62 ml, 5.4 mmoles) and 2.8 ml of potassium t-butoxide solution (1.0 M in THF) was added and the reaction stirred for 3 hours. Methyl toluenesulfonate (0.81 ml) and 1.4 ml of potassium t-butoxide solution were then added and the reaction was stirred for an additional 3 hours. The flask was removed from the oil bath and cooled to room temperature. The solution was transferred to a single-necked round bottom flask and the solvent was removed by rotary evaporation. The residue was dissolved in 5 ml of methylene chloride and precipitated by the addition of 50 ml of diethyl ether. The product was collected by filtration and dried under vacuum.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:28]C)[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:9]([NH2:30])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:30][C:9]1[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCNC3CCOCC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCCNC3CCOCC3)c2n1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-8-(methyloxy)-9-[5-(tetrahydro-2H-pyran-4-ylamino)pentyl]-9H-purin-6-amine (35.47 mg, 0.084 mmol) was stirred in methanol (2.3 ml) and treated with 4M HCl in 1,4 dioxane (0.527 ml, 2.109 mmol). The reaction was stirred in a capped vial overnight and then evaporated under nitrogen and the residue dissolved in 1:1 DMSO:MeOH (1 ml) and purified by Mass Directed AutoPrep (Method A). Product-containing fractions were combined and evaporated in a nitrogen blowdown unit to give the title compound as an off-white gum (23.28 mg).
Reaction SMILES: [I-].[F:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](N3C=C[N+](C)=C3)=[O:15])[CH2:10][C:9]2=[O:22])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:32]1([C:38]2([CH2:43][NH2:44])[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[C:45](OC)(=[O:50])[C:46](OC)=[O:47].[H-].[Na+]>CN(C=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]3[C:14](=[O:15])[N:44]([CH2:43][C:38]4([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:42][CH2:41][CH2:40][CH2:39]4)[C:46](=[O:47])[C:45]([OH:50])=[C:10]3[C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: NCC1(N2CCOCC2)CCCC1
Reactant: C[n+]1ccn(C(=O)N2CCN(Cc3ccc(F)cc3)C(=O)C2)c1
Reactant: COC(=O)C(=O)OC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2c(O)c(=O)n(CC3(N4CCOCC4)CCCC3)c(=O)n2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{[4-(4-fluorobenzyl)-3-oxopiperazin-1-yl]carbonyl}-3-methyl-1H-imidazol-3-ium iodide (75 mg, 0.17 mmol) in 1 mL of anhydrous DMF, under an atmosphere of nitrogen, was added triethylamine (28 μL, 0.20 mmol) and [(1-morpholin-4-ylcyclopentyl)methyl]amine (37 mg, 0.20 mmol) and stirred overnight at room temperature. Dimethyl oxalate (100 μL of 6.76 M DMF solution, 0.67 mmol) and sodium hydride (16 mg, 0.67 mmol) were added, and the reaction mixture was stirred at room temperature. The reaction was quenched with 4 mL of aq NH4Cl, diluted with water, followed by dropwise addition of 1N HCl until slightly acidic. The precipitated product was collected by filtration and rinsed with water, and diethyl ether. Drying under high vacuum provided the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 7.41 (dd, J=8.5, 5.6 Hz, 2H), 7.17 (bt, J=8.8 Hz, 2H), 4.68 (s, 2H), 4.06 (bs, 2H), 3.94 (bs, 2H), 3.59 (t, J=5.2 Hz, 2H), 3.51 (t, J=4.1 Hz, 4H), 2.64 (t, J=4.1 Hz, 4H), 1.7-1.4 (m, 8H). HRMS ES (M+1) calc'd for C24H30N4O5F; 473.2195 m/z. found 473.2193 m/z.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH:24]2[CH2:26][CH2:25]2)[CH2:18][C:17]3([CH3:28])[CH3:27])=[CH:8][C:7]=1[F:29])C.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH:24]1([N:19]2[CH2:18][C:17]([CH3:28])([CH3:27])[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:13]#[C:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:30])=[O:3])=[C:7]([F:29])[CH:8]=4)[CH:15]=3)[CH2:20]2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CN(C2CC2)Cc2ccc(C#Cc3ccc(CC(=O)O)c(F)c3)cc21

Procedure:
Following general procedure J and using [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylethynyl)-2-fluoro-phenyl]-acetic acid ethyl ester (Compound 21, 0.055 g, 0.135 mmol), methanol (2 mL), tetrahydrofuran (4 mL), water (1 mL) and lithium hydroxide monohydrate (0.117 g, 2.97 mmol) the title compound was obtained as a pale yellow solid foam (0.040 g, 78%).
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:23])C=1.[OH2:26]>C(Cl)Cl>[CH:1]1([S:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)(=[O:23])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: Brc1cccc(SC2CCCCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(=O)(c1cccc(Br)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 3-bromophenyl cyclohexyl sulfide (3.89 g) in DCM (200 ml) under nitrogen was treated with meta-chloroperbenzoic acid (57% pure, 8.69 g), and stirred at room temperature for 1.5 h. The reaction mixture was poured into water and washed with aqueous sodium sulphite until no peracid remained. The organic phase was washed with brine and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the title compound (3.63 g). LCMS RT=3.33 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=O)[CH2:4][C:5](OCC)=O.ClC1[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([F:24])=[CH:17][N:16]=1.Cl>CN(C)C=O>[F:24][C:18]1[CH:19]=[C:20]2[C:5]([CH2:4][C:3](=[O:11])[NH:21]2)=[N:16][CH:17]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Cc2ncc(F)cc2N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a dry flask was placed sodium hydride as a 60% suspension in oil (3.1 g, 77.5 mmol). Most of the oil was removed by washing twice with hexanes. The remaining solid sodium hydride was then suspended in dry dimethylformamide (DMF) (100 mL) and cooled to 0° C. Diethyl malonate (11.8 mL, 77.7 mmol) was then added dropwise with stirring. The mixture was stirred at 0° C. for 1 hour after which a solution of 2-chloro-5-fluoro-3-nitropyridine (5.21 g, 29.5 mmol) in DMF (40 mL) was added. Stirring at room temperature was continued overnight and the reaction mixture was poured into ice/water. Following acidification to pH 3 with 6N HCl solution, the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to leave a red oil. This was subjected to flash chromatography on silica gel using 3:7 ethyl acetate/hexanes, as eluant. All fractions containing the desired product were combined and concentrated to yield an oil containing 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine and diethyl malonate in a molar ratio of approximately 11:9 weighing 11.5 g. The yield of 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine was calculated to be approximately 8 g (90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[N-:12]=[N+]=[N-].[Na+]>CN(C)C=O>[NH2:12][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)ccn1
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of methyl 4-chloropicolinate and 2 g of sodium azide in 20 ml of dimethylformamide is stirred at 100° for 8 hours. The solvent is removed in vacuo, the reaction is diluted with water and the product extracted into ethyl acetate. After drying over magnesium sulfate, the solvent is removed in vacuo. The residue is hydrogenated in 30 ml of ethanol at atmospheric pressure over 500 mg of 10% palladium on carbon catalyst for 3 hours. After filtration through filter-cel the solvent is removed in vacuo and the residue crystallized from ether to afford methyl 4-aminopicolinate.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>C(OC(O)C)C>[F:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:12])[NH:6][CH:5]=[N:7]2)=[CH:14][CH:15]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Agent: CCOC(C)O
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Yield: 88.5 %

Procedure:
Formamidine acetate (31.2 g, 300 mmol) and 2-amino-4-fluorobenzoic acid (23.3 g, 150 mmol) are heated at reflux in ethoxyethanol for 16 h. The crude product is poured into saturate sodium bicarbonate solution. The solid is collected, washed, and dried, affording the titled 7-Fluoro-3H-quinazolin-4-one (21.8 g, 89%).
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]([O:17]C)=[N:15][C:14]2[C:9]1=[N:10][C:11]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:12][C:13]=2[NH2:19].C(N(CC)C(C)C)(C)C.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl-]>CN(C=O)C>[NH2:19][C:13]1[N:12]=[C:11]([O:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[N:10]=[C:9]2[C:14]=1[NH:15][C:16](=[O:17])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: COc1nc2c(N)nc(OC3CCCCC3)nc2n1CCCCCl
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(OC2CCCCC2)nc2c1[nH]c(=O)n2CCCCN1CCCCC1
Yield: 14.1 %

Procedure:
Sodium iodide (0.006 g, 0.04 mmol) was added to a stirred mixture of 9-(4-chlorobutyl)-2-(cyclohexyloxy)-8-(methyloxy)-9H-purin-6-amine (0.103 g, 0.303 mmol), N,N-diisopropylethylamine (0.105 ml, 0.079 g, 0.609 mmol) and piperidine (0.120 ml, 0.103 g, 1.215 mmol) in DMF (1.5 ml). The resultant mixture was heated at 80° C. for 20 hours when LCMS showed the formation of two products, one corresponding to displacement of the chloride by piperidine and the second corresponding to concomitant hydrolysis of the 8-methoxy moiety. The reaction mixture was partitioned between dichloromethane (6 ml) and water (6 ml) and the phases separated using a hydrophobic frit. The solvent was removed from the organic phase under a stream of nitrogen in a blow-down unit and the residue was dissolved in 1:1 MeOH:DMSO (2 ml) and separated by mass directed autopreparation (Method A) to afford the title compound as a white solid (16.6 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COCc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
A solution of methyl 3-cyano-5-(methoxymethyl)benzoate (184 mg, 0.75 mmol) in tetrahydrofuran (2.1 mL) was treated with 0.5 N lithium hydroxide (1.8 mL, 0.90 mmol). The reaction was stirred at 70° C. for 30 minutes and then after cooling the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 2 N hydrogen chloride until pH˜2-3. Following extraction of the aqueous layer with ethyl acetate, the organic layer washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 145 mg (quantitative) of 3-cyano-5-(methoxymethyl)benzoic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:21]([CH3:31])[CH:20]=1>>[ClH:1].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:27][CH2:26]2)=[C:21]([CH3:31])[CH:20]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Cc1cc(Cl)ccc1N1CCNCC1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3C)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-2-methyl-phenyl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CI.[CH:20]([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[CH3:1][O:2][C:3]([C@:5]1([CH3:20])[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH3:1][O:2][C:3]([C@@:5]1([CH3:20])[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Product: COC(=O)[C@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 4 h
Yield: 37.7 %
Yield: 18.9 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (500 mg, 2.04 mmol) and MeI (1.2 g, 8.45 mmol) in tetrahydrofuran at −40° C. was added a solution of lithium diisopropylamide in tetrahydrofuran (1.5M solution, 5 mL, 7.47 mmol). The reaction mixture was warmed to room temp. and stirred for 4 h. After completion of reaction, the mixture was re-cooled to −30° C. and quenched with saturated aqueous ammonium chloride. The reaction mixture was then extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to give two stereoisomers; (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (200 mg, 37.7% yield) and (2R,4R)-4-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (100 mg, 18.9% yield). MS calcd. for C12H22NO5 [(M+H)+] 260, obsd. 260.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:46][C:47]1[CH:51]=[C:50]([NH2:52])[NH:49][N:48]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:52][C:50]4[NH:49][N:48]=[C:47]([CH3:46])[CH:51]=4)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: Cc1cc(N)[nH]n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3cc(C)n[nH]3)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 101 mg, 0.283 mmol) in THF (5 mL) was added triethylamine (34.3 mg, 0.339 mmol), followed by the addition of 2,4,6-trichlorobenzoyl chloride (75.8 mg, 0.311 mmol). The suspension was stirred for 2 hours and then 3-methyl-1H-pyrazol-5-amine (35.7 mg, 0.367 mmol) was introduced. The reaction was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (10 mL). After phase-separation, the aqueous layer was extracted with EtOAc (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The residue was purified via silica chromatography (EtOAc/MeOH 20:1) to yield the title product (23 mg, 19%). LCMS (apci) m/z=437.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]([OH:19])=O)=[CH:10][C:9]2=1)(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][OH:59])[CH2:53]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[OH:59][CH2:58][CH:54]1[O:55][CH2:56][CH2:57][N:52]([C:17]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[NH:15][C:16]2[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:7][C:8]3=2)=[O:19])[CH2:53]1
Reactant: COc1ccccc1-c1cc(C(N)=O)c2[nH]c3ccc(C(=O)O)cc3c2c1
Reactant: OCC1CNCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(C(N)=O)c2[nH]c3ccc(C(=O)N4CCOC(CO)C4)cc3c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
8-Carbamoyl-6-(2-methoxyphenyl)-9H-carbazole-3-carboxylic acid (31.5 mg, 0.061 mmol), HATU (75 mg, 0.197 mmol), DMAP (25 mg, 0.205 mmol), morpholin-2-ylmethanol (35 mg, 0.299 mmol) and DMF (3 ml) were combined and stirred at room temperature for 18 hours. The reaction mixture was filtered through a 0.45 um Nylon filter and purified by prep HPLC chromatography (water/CH3CN/NH4OAc eluent system). Product containing fractions were collected and evaporated in SPEEDVAC®. 13.4 mg 6-(2-(hydroxymethyl)morpholine-4-carbonyl)-3-(2-methoxyphenyl)-9H-carbazole-1-carboxamide were isolated as an off-white solid. MS (ESI) m/z 460 [M+H]. 1H NMR (CD3OD) δ ppm 8.45 (d, 1H, J=1.5), 8.27 (bs, 1H), 8.09 (d, 1H, J=1.5), 7.71 (d, 1H, J=8.6), 7.56 (dd, 1H, J=8.4, 1.7), 7.47 (dd, 1H, J=7.5, 1.7), 7.37 (dt, 1H, J˜8, ˜8, 1.7), 7.14 (d, 1H, J=8.5), 7.09 (dt, 1H, J=0.9, 7.5, 7.5), 4.05-3.90 (b, 2H), 3.86 (s, 3H), 3.70-3.55 (b, 4H), 3.5-3.0 (b, 3H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([O:11][C:12](=[O:34])[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:31][CH2:32][CH3:33])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:7]([O:11][C:12](=[O:34])[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:31][CH2:32][CH3:33])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)C(=O)Cl
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isobutyryl chloride (38 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C27H35N3O3+H: 450, observed: 450.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH2:19][OH:20])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([O:33][C@@H:34]([CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:32]>>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([C:13]2[CH:14]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][C:44]3[CH:43]=[CH:42][C:41]([CH2:40][C@H:34]([O:33][CH2:31][CH3:32])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:46][CH:45]=3)[CH:16]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)[CH:12]=2)=[CH:22][CH:23]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(-c2cc(/C=C/CO)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccc(C(C)(C)C)cc3)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1)OCC
Yield: 79.3 %

Procedure:
The title compound (368 mg, 79%) was prepared from (E)-3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-prop-2-en-1-ol (300 mg, 0.75 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (188 mg, 0.79 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23])=[O:19].CC1C=CC(S(O)(=O)=O)=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCN(CC)CC>[N:8]1([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:23])=[O:19])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of Boc-L-Proline (1.43 g, 6.7 mmol) and Gly-Gly-Gly-OCH2Ph.TsOH (3.0 g, 6.7 mmol) in CH2Cl2 (40 mL) and Et3N (2.80 mL) was cooled to 5° C. and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.34 g, 7.0 mmol) was added. The reaction was stirred at ambient temperature for 3 days and then the solvent was evaporated. The crude material was dissolved in ethyl acetate (50 mL) and washed with saturated aqueous NH4Cl (25 mL), brine (25 mL), dried over MgSO4, and then evaporated to dryness. The product was purified by column chromatography (SiO2, CH2Cl2-MeOH 95:5) to give Boc-Pro-Gly-Gly-Gly-OCH2Ph (SEQ ID NO.: 1) (2.25 g, 71%) as colorless crystals, mp 54–55° C. 1H-NMR (300 MHz, δ, CDCl3): 1.42 (9H, s), 1.80–2.20 (4H, m), 3.35–3.55 (2H, m), 3.85–4.20 (7H, m), 5.15 (2H, s), 7.05 (2H, bs), 7.30–7.35 (5H, m), 7.80 (1H, bs). 13C-NMR (75 MHz, δ, CDCl3): 24.6, 28.3, 29.4, 41.1, 43.0, 43.3, 47.2, 60.7, 66.9, 80.9, 128.4, 128.5, 128.7, 135.4, 155.8, 169.6, 170.0, 173.9. IR (KBr, cm−1):, 1753(CO), 1667(CO).