Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:9]([CH:14]=1)[C:10](OC)=[O:11])(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:9]([CH:14]=1)[CH2:10][OH:11])(=[O:3])=[O:4]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(CO)c1
Yield: 34 %

Procedure:
To a solution of methyl 5-methanesulfonyl-2-(morpholin-4-yl)benzoate obtained in Step 3 in tetrahydrofuran (300 ml) was added lithium aluminum hydride (3.6 g, 94 mmol) by small portions under ice-cooling. After stirring under ice-cooling for 1 hr, 1N hydrochloric acid (200 ml) was slowly added and the mixture was stirred at room temperature for 1 hr. After extraction with ethyl acetate (500 ml), the organic layer was washed with saturated brine (200 ml×3), and dried over magnesium sulfate. After filtration and concentration, the resulting solid was collected by filtration. The solid was washed with a mixed solvent (100 ml) of hexane-ethyl acetate (4:1) to give 5-methanesulfonyl-2-(morpholin-4-yl)benzyl alcohol (8.6 g, yield 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:31][CH2:32][CH2:33][C:34]#[N:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][C:34]#[N:35])[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: N#CCCNCc1ccccc1
Product: COc1ccccc1N(CC(=O)N(CCC#N)Cc1ccccc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-benzylamino-propionitrile
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[CH2:4][CH2:3]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:49][CH2:50][O:51][CH2:52][CH2:53]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((3-morpholinopropylamino)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (69 mg, 0.095 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 3 h then was concentrated under reduced pressure. The residue was purified by prep. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound (36 mg, 0.054 mmol, 56.5% yield) as a white foam. LCMS: m/e 671.5 (M+H)+, 2.17 min (method 6). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=8.03 Hz, 2H),7.15 (d, J=8.03 Hz, 2H), 5.29 (d, J=4.52 Hz, 1H), 4.71 (br. s., 1H), 4.62 (br. s., 1H), 3.73 (br. s., 4H), 3.09-3.26 (m, 3H), 2.65 (d, J=12.30 Hz, 1H), 2.56 (br. s., 6H), 2.42 (br. s., 1H), 1.69 (s, 3H), 1.07 (s, 3H), 1.05-2.14 (m, 24H), 1.00 (s, 3H), 0.97 (s, 3H), 0.93 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)[CH:11]=[N:12][CH:13]=2)=[C:6]([NH:25][C@H:26]([C:28]2[N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32](=[O:40])[C:31]3=[C:41]([CH3:44])[CH:42]=[CH:43][N:30]3[N:29]=2)[CH3:27])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:11]=[N:12][CH:13]=2)=[C:6]([NH:25][C@H:26]([C:28]2[N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32](=[O:40])[C:31]3=[C:41]([CH3:44])[CH:42]=[CH:43][N:30]3[N:29]=2)[CH3:27])[N:5]=[CH:4][N:3]=1
Reactant: COc1cccc(C(=O)Nc2cncc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(NC(=O)c4cccc(O)c4)c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
(S)—N-(5-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)pyridin-3-yl)-3-methoxybenzamide (95 mg, 0.16 mmol) was dissolved in dichloromethane (3 ml). A solution of boron tribromide (1M in dichloromethane, 480 μl, 0.48 mmol) was added dropwise and the reaction was stirred at room temperature overnight. More solution of boron tribromide (1M in dichloromethane, 240 μL, 0.24 mmol) was added and the reaction was stirred at room temperature for 4 h. The mixture was diluted with dichloromethane and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 45 mg (49% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)[CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:9]=1)[CH3:3]
Reactant: Cc1ccc(C(C)O)cc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl [5-(1-hydroxyethyl)-2-methylphenyl]carbamate (2.39 g) in ethyl acetate (47.5 mL) was added 10% palladium on carbon (56.5% water included, 1.10 g), and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite (registered trademark) pad. The filtrate was concentrated under reduced pressure to obtain the title compound (2.23 g). 1H-NMR (DMSO-d6) δ ppm: 1.14 (3H, t, J=7.5 Hz), 1.45 (9H, s), 2.13 (3H, s), 2.53 (2H, q, J=7.5 Hz), 6.82-6.90 (1H, m), 7.05 (1H, d, J=7.8 Hz), 7.11-7.18 (1H, m), 8.42 (1H, s).
Reaction SMILES: ClC1C=CC(C[N:7]2[C:19]3[CH:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=2)[C:12]=3CC=C)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:48][C:49]1C=CC2C(=CC=CC=2)N=1.Cl>CN(C=O)C.O>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:27][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:19]1[CH:18]([CH2:20][C:21]([O:23][CH2:48][CH3:49])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: C=CCc1c(OCc2ccc3ccccc3n2)ccc2c1c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCCc2c1[nH]c1ccc(OCc3ccc4ccccc4n3)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the phenol ester of Example 9, Step 2 (8.86 g, 32.4 mmol) in anhydrous DMF (50 ml) was added K2CO3 (6.72 g, 48.6 mmol) followed by 2-(chloromethyl)quinoline (7.49 g, 42.1 mmol). The mixture was stirred for 48 hours at room temperature. 2N HCl was added carefully until neutral to litmus paper. H2O (300 ml) was added and the mixture was extracted with EtOAc (6×100 ml). The combined organic layers were washed with water (400 ml) and dried over MgSO4. Evaporation and flash chromatography (20% EtOAc in hexane) afforded ethyl 6-(quinolin-2-ylmethoxy)-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][N:31]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[CH3:16])=[O:13])[CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C)CC2)c(C2CC2)c1
Yield: 43.6 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (217 mg) described in Preparation Example 86 and by the reaction and treatment in the same manner as in Example 87, the title compound (198 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH:5]23.C(N(CC)CC)C.[C:26]12([C:36](Cl)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.O>C(#N)C.CN(C)C1C=CN=CC=1>[C:26]12([C:36]([O:1][CH:2]3[CH:6]4[O:7][C:8](=[O:18])[CH:9]5[CH:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:3]3[CH2:4][CH:5]45)=[O:37])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
In 2,000 ml of acetonitrile were dissolved 282 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furan-7-carboxylate (21), 157 g of triethylamine and 13.6 g of 4-dimethylaminopyridine. Below 20° C., 328 g of adamantanecarboxylic chloride (26) was added dropwise to the solution, which was stirred at room temperature for 3 hours. Then 1,000 g of water was added to the solution, followed by standard work-up. Recrystallization from methylene chloride gave 391 g of the target compound (yield 85%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[BrH:14].N([O-])=O.[Na+].[Br-]>O.C(OCC)C>[Br:14][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: Br
Agent: O=N[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
To the solution of 7.92 g (43 mmol) 3-amino-5-nitro-benzoic acid in 4 ml water in an ice bath 48.8 ml (434 mmol, 10 eq) of aq 48% HBr are added. A saturated aqueous solution of 4.05 g (59 mmol, 1.35 eq) sodium nitrit is added over 10 min. The obtained solution is added to the solution of 9.36 g (65 mmol, 1.5 eq) cupper bromide in 48.8 ml (434 mmol, 10 eq) of aq 48% HBr at 70° C. The mixture is heated for 45 min at 70° C. After cooling to rt diethylether is added and the organic layer is washed with water until neutral pH is reached. Drying over sodium sulfate and evaporation of the solvent at reduced pressure to give the product as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([O:14][CH:15]([C:17]([O:19]CC)=[O:18])[CH3:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+]>C(O)C>[C:17]([CH:15]([O:14][C:11]1[N:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1)[CH3:16])([OH:19])=[O:18]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1)C(=O)O

Procedure:
Four g of the compound of Example 6 was refluxed for 4 hours with 1.4 g of potassium hydroxide in 75 ml of ethanol, and the product was collected as shown in Example 22 and recrystallized from ethanol to obtain 3.3 g of the desired product, m.p. 222°-224°.
Reaction SMILES: C1(N2CCN3C(CC4(C5C=CC=CC=5)CCCC4)=NC(=O)C(O)=C3C2=O)CC1.C([O:36][C:37]1[C:42](=[O:43])[N:41]=[C:40]([CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][CH2:47][CH2:46]2)[N:39]2[CH2:56][CH2:57][N:58]([CH:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)[C:59](=[O:60])[C:38]=12)C1C=CC=CC=1>>[OH:36][C:37]1[C:42](=[O:43])[N:41]=[C:40]([CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][CH2:47][CH2:46]2)[N:39]2[CH2:56][CH2:57][N:58]([CH:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)[C:59](=[O:60])[C:38]=12
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CCOCC1
Agent: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CCOCC1
Yield: 90.4 %

Procedure:
This compound was prepared following the same method as described for 2-cyclopropyl-9-hydroxy-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (287) from 9-benzyloxy-6-(1-phenyl-cyclopentylmethyl)-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (310) (240 mg, 0.47 mmol). The product was obtained as a white solid (180 mg, 90.96%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:38])([CH3:39])[CH2:36][CH3:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(C(=O)N3CCOCC3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
Following the same procedure in Example 3, Step A, using morpholine (26.1 mg, 0.30 mmol), diisopropylethylamine (69.7 μL, 51.7 mg, 0.40 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (65.7 mg, 0.20 mmol)) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (91.3 mg, 0.24 mmol). The mixture was stirred overnight at room temperature, added H2O (50 mL), extracted with EtOAc (3×50 mL). The desired title compound was purified by reversed-phase HPLC (C-18 column) using 10-50% CH3CN/H2O to give 82.1 mg (80%) of a white solid. 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.42 Hz, 3 H), 1.27 (m, 5 H), 1.65 (m, 3 H), 1.69 (s, 6 H), 1.78 (m, 2 H), 2.04 (q, J=7.42 Hz, 2 H), 2.12 (m, 1 H), 3.47 (m, 2 H), 3.62 (m, 2 H), 3.79 (m, 4 H), 4.50 (d, J=7.62 Hz, 2 H), 7.66 (dd, J=8.69, 1.46 Hz, 1 H), 7.82 (d, J=0.78 Hz, 1 H), 8.01 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H)+=398.3. Anal. Calcd for C24H35N3O2+1.60 TFA+1.10 H2O+0.30 MeCN (612.14): C, 54.55; H, 6.54; N, 7.55. Found: C, 54.61; H, 6.53; N, 7.51.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8]O)[N:5]([NH2:10])[C:4]=1[CH3:11].S(Cl)([Cl:14])=O>ClCCl>[Cl-:14].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8][Cl:1])[N:5]([NH2:10])[C:4]=1[CH3:11]
Reactant: Cc1n(N)c(CO)c[n+]1N
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1n(N)c(CCl)c[n+]1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.8 g (21.3 mmol) of 1,3-diamino-4-(hydroxymethyl)-2-methylimidazolium chloride are taken up in 200 ml of dichloromethane and treated with 2.56 g (21.3 mmol) of thionyl chloride. The mixture is stirred at room temperature for 3 days, the product is filtered off, washed with dichloromethane and dried at 40° in a high vacuum. There is obtained 1,3-diamino-4-(chloromethyl)-2-methylimidazolium chloride of melting point 163°-165°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23](O)[C:24]([OH:26])=[O:25])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)(=O)C.S(=O)(=O)(O)O>[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23]([C:8]1[CH:7]=[C:5]([OH:6])[C:4]([OH:9])=[CH:3][C:2]=1[Br:1])[C:24]([OH:26])=[O:25])=[O:21]
Reactant: CCN1CCN(C(=O)NC(O)C(=O)O)C(=O)C1=O
Reactant: Oc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)O)c2cc(O)c(O)cc2Br)C(=O)C1=O
Reaction time: 18 h

Procedure:
4-Bromocatechol (4.77 g, 25.2 mmole) was added to an ice bath cooled suspension of N-(2,3-dioxo-4-ethylpiperazin-1-yl-carbonyl)-2-hydroxyglycine (2.59 g. 10 mmole) in glacial acetic acid (9 ml) and concentrated sulphuric acid (1 ml). The mixture was stirred for 18 hours then poured onto a mixture of ice, saturated sodium carbonate and ethyl acetate and adjusted to pH7 with sodium carbonate. The aqueous layer was collected, washed with ethyl acetate (50 ml), acidified to pH1 and extracted with ethyl acetate (3×50 ml). The extracts were dried and evaporated in vacuo to a buff solid, 2.4 g, 79%, δ[(CD3)2CO]1.13(3H, t, J7 Hz, CH2CH3), 3.57(2H, q, J7 Hz, CH2CH3), 3.5-4.3(4H, m, 2×NCH2), 5.3-7.6(3H, broad, 2×OH, CO2H), 5.73 (1H, d, J6.5 Hz, CHNH), 6.87 and 7.03 (2H, 2×s, Ar), 9.73(1H, d, J6.5 Hz, CHNH).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([CH:31]2[CH2:35][CH2:34][C:33]([CH3:37])([OH:36])[CH2:32]2)=[CH:29][CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1.O>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([CH:31]3[CH2:35][CH2:34][C:33]([CH3:37])([OH:36])[CH2:32]3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: CC1(O)CCC(c2cccnc2F)C1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(O)CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 180 °C

Procedure:
To a 20 mL microwave vial was added cesium carbonate (1460 mg, 4.48 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (565 mg, 2.331 mmol), and 3-(2-fluoropyridin-3-yl)-1-methylcyclopentanol (350 mg, 1.793 mmol) as a solution in NMP (3585 μL). The reaction mixture was heated to 180° C. for 3 h with microwave irradiation. The reaction was diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure to a dark brown oil. Three purifications of the diastereomeric mixture by SFC gave four compounds. MS (ESI, pos. ion) m/z: 418.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][CH2:43][C@H:42]5[CH2:46][O:47][Si](C(C)C)(C(C)C)C(C)C)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][CH2:43][C@H:42]5[CH2:46][OH:47])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H]5CO[Si](C(C)C)(C(C)C)C(C)C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H]5CO)n4c3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of Intermediate 28d (38 mg, 0.048 mmol) in THF (1 mL) at −30° C. was added TBAF (1M in THF, 72 μL, 0.072 mmol) and the mixture was allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph column, 10-70% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (12 mg, 39%). LCMS (Method 5): Rt 4.20 min, m/z 635 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.29 (9H, s), 1.78-2.28 (8H, m), 2.38 (3H, s), 3.36-3.46 (1H, m), 3.53 (2H, dd, J 5.0, 1.6), 3.64-3.73 (1H, m), 4.04-4.12 (1H, m), 4.85-4.91 (1H, m), 5.36 (1H, t, J 4.1), 6.32 (1H, s), 7.11 (1H, dd, J 10.0, 2.1), 7.20-7.35 (8H, m), 7.44 (1H, d, J 9.9), 7.99-8.01 (1H, m).
Reaction SMILES: C(O)=O.C(OC(=O)[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[O:18][C:19]3[CH:25]=[C:24]([O:26][C:27]4[S:28][C:29]5[C:30]([N:35]=4)=[N:31][CH:32]=[CH:33][CH:34]=5)[CH:23]=[CH:22][C:20]=3[CH:21]=2)[CH2:12]1)(C)(C)C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[S:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:35]=[C:27]1[O:26][C:24]1[CH:23]=[CH:22][C:20]2[CH:21]=[C:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:11]([NH2:10])[CH2:12]3)[O:18][C:19]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Agent: Cl
Solvent: O=CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
To a suspension of {1-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-ylmethyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester formate (435 mg, 0.849 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (1.06 mL, 4.25 mmol) and the reaction mixture was stirred (rt, 14 h). The reaction mixture was concentrated in vacuo to afford the title compound as a yellow solid (320 mg, 95%). MS (ESI): mass calcd. for C19H18N4O2S, 366.1; m/z found, 367.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[Cl:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([N:16]([CH2:15][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:4][CH2:3]1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:38]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: COc1ccc(CNCC2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(Cl)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a mixture of tert-butyl 4-hydroxy-4-[[(4-methoxyphenyl)methylamino]methyl]piperidine-1-carboxylate (1.06 g, 3.01 mmol) and diisopropylethylamine (1 mL, 5.74 mmol) in DCM (15 mL) at 0° C. was added 2-chloro-2-phenyl-acetyl chloride (654 mg, 3.46 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give tert-butyl 4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.11 g, 73%) as a pale yellow oil. ESI-MS m/z calc. 502.2. found 503.5 (M+1)+; Retention time: 1.90 minutes (3 min run).