Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.[Li:16]C(C)(C)C.CCCCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Li:16]
Reactant: [Li]C(C)(C)C
Reactant: Fc1cccc(Oc2ccccc2Br)c1
Solvent: CCCCC
Solvent: C1CCOC1
Product: [Li]c1ccccc1Oc1cccc(F)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(3-fluorophenoxy)-2-bromobenzene (1.27 g, 4.75 mmol) in THF (10 mL) at −70° C. was added 1.7 M t-BuLi in pentane (5.6 mL, 9.50 mmol) dropwise to keep the temperature below −70° C. The resulting solution was stirred at −70° C. for 30 min, and used for the next step directly.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:23][CH3:24])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]([CH3:25])[CH3:24])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CNn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 56.3 %

Procedure:
A mixture of 6-chloro-2-methylamino-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (800 mg), potassium carbonate (400 mg), methyl iodide (20 ml) and DMF (20 ml) was stirred at 80° C. for 3 days. The reaction mixture was concentrated, and ethyl acetate was added to the obtained residue. The mixture was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) and crystallized from isopropyl ether to give the title compound (469 mg) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(#N)C.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 ml), treated with potassium carbonate (16 mg, 0.12 mmol) and morpholine (10 gut, 0.11 mmol), and stirred 18 hours at room temperature. The reaction was heated to 50° C. for 8 hours, and then was allowed to stir 18 hours at room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to an oil which was purified by reverse phase HPLC to yield 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-morpholinoethoxy)benzamide. MS (Q1) 530 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].Cl>O.CC(C)=O>[C:2]1([NH:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
N-phenylbenzamide (Structure II) is synthesized from aniline and benzoyl chloride using acetone as a reaction media and an aqueous solution of NaOH to neutralize the HCl generated. A 20 ml aqueous solution of NaOH (2.57 grams, 0.064 moles) and 6.0 grams (0.064 moles) of aniline are first added to a stirred 250 ml flask containing 75 ml of acetone. Benzoyl chloride (9.06 grams, 0.064 moles) is next added over a five minute period. This reaction mixture which now contains a white precipitate is stirred for 1.5 hours and then diluted with 50 ml of deionized water. This solution is next filtered and the filter cake obtained is sequentially washed with 50 ml of deionized water (two times) followed by 50 ml of methanol. The washed filter cake is recovered and DCS analysis of this product showed a sharp melting endotherm at 169° C. ##STR10##
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[CH2:14]([S:21](Cl)(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.Cl>[OH-].[Na+].O1CCOCC1>[CH2:14]([S:21]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in 1N aqueous sodium hydroxide (10 ml)-dioxane (3 ml), and dioxane (7 ml) solution of benzylsulfonylchloride (1.91 g, 10 mmole) was added dropwise to the solution while cooling with ice and stirring while keeping pH value thereof to between 10 and 11 using 1N aqueous sodium hydroxide. After completion of the addition, the mixture was further stirred for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 1.5 with 1N aqueous hydrochloric acid while cooling with ice and stirring to precipitate N-benzylsulfonyl-L-alanyl-L-proline in a crystalline form[yield: 1.78 g, 52.3%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:18]1[S:19][CH:20]=[CH:21][N:22]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C@@H:14]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[OH:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)c1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1nccs1
Reaction time: 48 h
Yield: 4.6 %

Procedure:
To a solution of 10.8 g of t-butoxycarbonyl-L-leucinal in 40 of dichloromethane was added 9.4 g of 2-trimethylsilyl thiazole in 10 ml of dichloromethane. The reaction was allowed to stand for 48 hours, then was cooled in an ice bath and treated cautiously with 30 ml of 1M tetra-n-butylammonium fluoride in tetrahydrofuran. This mixture was refluxed for 1.5 hours and then concentrated to an oil. The oil was dissolved in 100 ml of ethyl acetate, washed with 50 ml each of 2N citric acid, 1M sodium bicarbonate and brine and dried. The solution was treated with activated carbon, filtered through a pad of hydrous magnesium silicate and concentrated to an oil. This oil was dissolved in 50 ml of 10% ethyl acetate in dichloromethane and chromatographed on two columns in the same solvent. Refractive index was monitored at S 20, 250 ml/minute. The main peak in hold-back volumes 6-10 was cut into 1 liter portions which were separately evaporated. The first three of these all crystallized and the solids were recrystallized form isopropyl ether and hexane, giving 0.7 g of (S)2-(t-butoxycarbonyl)amino-4-methyl-(S)1-(2-thiazolyl)pentan-1-ol as crystals, mp 121°-122° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[C:16](=[N:17][C:18]([C:24]5[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=5)=[CH:19]4)[C:15]=3[CH:31]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:33].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([S:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[CH:19]=[C:18]([C:24]5[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=5)[N:17]=[C:16]4[C:15]=3[CH:31]=2)=[O:33])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccnc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidin-4-ylsulfanyl)-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 12 (138 mg, 0.317 mmol) in DCM (20 mL) was added TFA (122 μL, 1.59 mmol) followed by a solution of m-CPBA (60 mg, 0.349 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 5-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 223 as a colorless foam (114 mg, 80%). LCMS: RT1.94 min [M+H]+ 501.0. 1H NMR (DMSO, 400 MHz): δ 8.70 (1H, d, J=2.27 Hz), 8.38 (1H, d, J=4.97 Hz), 7.92 (1H, s), 7.81 (1H, s), 7.50 (1H, dd, J=8.51, 2.30 Hz), 7.23 (1H, d, J=8.51 Hz), 7.07 (1H, d, J=5.03 Hz), 4.59-4.50 (4H, m), 2.86-2.78 (2H, m), 2.74-2.58 (2H, m), 2.39 (3H, s), 2.15-2.01 (2H, m), 1.76 (1H, bd, J=12.05 Hz), 1.59-1.43 (3H, m), 0.90 (6H, d, J=6.53 Hz)
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C(#N)C>[OH:24][C:22]([CH2:21][N:20]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:23]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: NCC(=O)O
Solvent: CC#N
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(=O)O

Procedure:
5.2 g (0.02 mol) of 6-phthalimido-2,5-hexanedione and 1.6 g (0.02 mol) of glycine are stirred in 50 ml of acetonitrile at 80° C. for 1 hour. After the mixture has been concentrated, it is extracted under alkaline conditions with methylene chloride and the extract is acidified and extracted again. The resulting product is recrystallised from methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:58][CH2:59][C:60]([OH:62])=[O:61]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([S:58][CH2:59][C:60]([OH:62])=[O:61])=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(O)CS
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)SCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reaction time: 8 h

Procedure:
To a solution of 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acid (for reference procedure see Example 18, WO2010/089107, which is incorporated herein by reference in its entirety) (0.2 g, 0.519 mmol), in dry DMF (6 ml), HATU (0.198 g, 0.521 mmol) and 4-methylmorpholine (0.057 ml, 0.521 mmol) were added and the mixture was stirred at RT until the complete conversion of the carboxylic acid into the activated ester occurred. 2-mercaptoacetic acid (0.030 ml, 0.434 mmol) was then added drop-wise, and the reaction mixture was stirred in the same conditions overnight. DMF was removed under reduced pressure and the crude was partitioned between EtOAc and HCl 1N; the organic layer was dried over Na2SO4, and the resulting crude was purified by trituration with Et2O affording 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoylthio)acetic acid as an off-white solid containing some impurities (0.253 g, yield supposed to be quantitative, MS/ESI+ 459.7 [MH]+). The product was used for the next step without any further purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.CI>CN(C)C=O>[Cl:7][C:8]1[C:9]([N:23]([CH3:1])[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: CC(C)(C)[O-]
Reactant: CCS(=O)(=O)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCS(=O)(=O)N(C)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
Potassium tert-butoxide (67.5 mg, 1.1 mmol) was added to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)ethanesulphonamide (Preparation 4) (200 mg, 0.55 mmol) in dry dimethylformamide (3 ml) under nitrogen at 20° C. After 5 minutes, methyl iodide (38 μl, 1.1 mmol) was added and the mixture was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate and water, and the combined organic extracts were washed with dilute aqueous sodium hydroxide. The solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane) to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methyl)ethanesulphonamide (150 mg, 79%).
Reaction SMILES: [Cl-:1].[NH:2]([C:4](=[O:12])[CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:3].[CH:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]=O)=[CH:15][CH:14]=1>C(O)C>[Cl-:1].[O:12]=[C:4]([NH:2]/[N:3]=[CH:21]/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)[CH2:5][N+:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: NNC(=O)C[n+]1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: O=C(C[n+]1ccccc1)N/N=C/C=C/c1ccccc1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A mixture of 4a (1.5 g, 8.0 mmol) and trans cinnamic aldehyde (1.6 g, 12.0 mmol) in ethanol (20 ml) was heated under reflux for 3 h. After cooling to room temperature, the mixture was filtered, and the residue dried under vacuum (0.6 mbar) to give 0.51 g (21%) of a pale-yellow solid consisting of two isomers with respect to the amide bond conformation (E:Z ca. 3:1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2cc(F)cc(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidin-1-carboxylate (1.57 g, 4.77 mmol) in dichloromethane (20 ml), was added trifluoroacetic acid (5 ml). The mixture was stirred for 1 h at ambient temperature after which the solvent was evaporated. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (0.845 g, 77%). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 169-170° C. MS m/z (rel. intensity, 70 eV) 199 (bp), 187 (93), 157 (61), 133 (66), 129 (59).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCNCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)[C@@H](O)CC[C@@H]12)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL CH2Cl2 is added 22.5 mL (0.217 mmol) diethylamine. The reaction mixture is stirred at room temperature for 2 hours 30 minutes and then concentrated in vacuo to give an orange paste. The residue is dissolved in ethyl actate (EtOAc) and precipitated with hexane. The precipitate is washed two times with hexane to give 45 mg (77%) product as an orange solid. HRMS (ESI) m/z calcd for C27 H37NO8 503.25206, found: 504.25747 (M+H)+1.
Reaction SMILES: ClC1C(OC)=C(OC)C=CC=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36]Cl)[C:24]2[CH:38]=[CH:39][CH:40]=[CH:41][C:23]=2[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13].[Na+].[I-].C[C:45]([CH3:47])=O>>[CH3:19][CH:17]([CH3:18])[CH2:16][CH2:15][N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36][N:22]2[CH2:47][CH2:45][N:14]([CH3:12])[CH2:20][CH2:21]2)[C:24]2[CH:38]=[CH:39][CH:40]=[CH:41][C:23]=2[N:22]=1)[CH:12]=[O:13]
Reactant: CC(C)=O
Reactant: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3n2Cc2ccccc2OCCCCl)c(Cl)c1OC
Agent: [I-]
Agent: [Na+]
Product: CC(C)CCN(C=O)Cc1nc2ccccc2n1Cc1ccccc1OCCCN1CCN(C)CC1
Temperature: 25 °C

Procedure:
A solution of 395 mg (0.66 mmole) of (2-chloro-3,4-dimethoxyphenyl)-N-[(1-{[2-(3-chloropropoxy)phenyl]-methyl}benzimidazol-2-yl)methyl]-N-(3-methylbutyl) carboxamide in 6 mL of acetone is treated with 99 mg (3.30 mmole) of NaI at reflux for 16 hrs, at which time another 3.30 mmole of NaI is added and heated for an additional 24 hrs. The solution is evaporated under reduced pressure, the residue is diluted with 30 mL of ethyl acetate, washed with 2×10 mL water and 1×10 mL brine, dried over anhydrous Na2SO4 and the solvent is removed in vacuo. The residue is dissolved in anhydrous 1-methyl-2-pyrrolidinone at 100 mg/ mL and 1 mL of the solution is treated with an excess of N-methyl piperazine at 50° C. for 16 hr. The resulting solution is cooled to room temperature, washed with 3×1 mL water and 1×1 mL brine, dried over anhydrous Na2SO4 and the solvent is removed in vacuo. The residue is prep-plate chromatographed (5% MeOH/CH2Cl2/0.5% NH4OH) to afford 65 mg (70%) of 2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[1-({2-[3-(4-methylpiperazinyl)propoxy]phenyl}methyl)benzimidazol-2-yl]methyl}carboxamide. Mass Spec M+ 663.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].CN(C(ON1N=[N:40][C:35]2C=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCCC1>CN(C=O)C>[N:40]1([C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:24])=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)=[O:21])[CH2:37][CH2:38][CH2:39][CH2:34][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(C(=O)N3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 30 mg (0.10 mmol) 4-((4-(2-acetamidopropyl)phenyl)ethynyl)benzoic acid (I72.2) in 1 mL DMF are added 20.0 μl (0.10 mmol) TEA and 50 mg (0.15 mmol) TBTU. The mixture is stirred at r.t. for 5 min before it is added to 10 mg (0.12 mmol) piperidine in 500 μl DMF. After stirring at r.t. for 72 h the mixture is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-(trifluoromethoxy)phenylboronic acid (Lancaster Synthesis Ltd.) (51 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as an orange glass. MS (ESI, pos. ion) m/z: 389 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:17])[NH:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[H][H]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Yield: 114.6 %

Procedure:
Dissolve 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.7 g 1.00 equiv; 39.9 mmoles) in methanol (300 mL) and add acetic acid (2 equiv, 79.73 mmoles; 4.6 mL), and methanol washed Raney Nickel (2.7 g). Heat the reaction to 50° C., then hydrogenate with 1 ATM hydrogen gas for 4.5 hours. Filter the reaction mixture through Celite and concentrate under reduced pressure. Suspend the solid in diethyl ether, filter and dry under reduced pressure to give 10.39 g of 4-carbamimidoyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:39])[CH2:37][CH3:38]
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(OC)cc(N5CCN(C)CC5)c4o3)cc2)CC1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available propionyl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=534 by positive ion CI