Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH:23]([OH:25])[CH3:24])=[CH:18][C:17]=3[Cl:26])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:17]1[CH:18]=[C:19]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:40]#[C:39][C:37]([OH:41])([CH3:38])[CH3:36])[CH:28]=[CH:27][C:5]=2[N:6]=1
Reactant: C#CC(C)(C)O
Reactant: CC(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)c1cc(Cl)c(Nc2nc3ccc(C#CC(C)(C)O)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 65 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (292 mg, 0.61 mmol) in DMF (3 mL) were added triethylamine (0.255 mL, 1.83 mmol), copper iodide (23 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol), and 2-methyl-3-butyn-2-ol (0.179 mL, 1.83 mmol). The solution was degassed by bubbling nitrogen gas and heated to 65° C. for 14 hr. The solution was diluted with EtOAc and washed with water, dried with Na2SO4, filtered, and concentrated under reduced pressure. Purification with column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) provided 5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}-9-(3-hydroxy-3-methylbut-1-yn-1-yl)benzo[c]-2,6-naphthyridin-1(2H)-one as a mixture of enantiomers. The enantiomers were separated on Chiral Technology AD 2×25 cm column at 12 mL/min using 1:1 iPrOH/Heptane in a 25 min run. First enantiomer has a retention time of 7.57 min and the second enantiomer has a retention time of 15.74 min. For both enantiomers: 1H NMR (500 MHz, CD3OD) δ 9.80 (d, 1H), 7.60 (d, 1H), 7.50-7.40 (m, 3H), 7.34 (d, 1H), 3.90 (m, 1H), 1.48 (s, 3H), 1.47 (s, 3H), 1.12 (d, 3 H). LRMS (ESI) calc'd for C25H22Cl2N3O3 [M+H]+, 482.1; found 482.1.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)[C@H:5]([OH:23])[CH2:6][NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:33](C1NC=CN=1)(=[O:35])[CH3:34].CO.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([F:31])[CH:28]=1)[CH2:24][C@H:4]([NH:3][C:33](=[O:35])[CH3:34])[C@H:5]([OH:23])[CH2:6][NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(=O)c1ncc[nH]1
Reactant: CC(C)c1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reaction time: 0.25 h

Procedure:
The free base of compound 6 (1.6 g, 3.8 mmol) is dissolved in 20 mL of CH2Cl2 under nitrogen, and 0.87 g (7.9 mmol) of acetyl imidazole is added with stirring. After 15 min., 30 mL of methanol is added, followed by 15 mL of 1 N NaOH to saponify the ester that is formed along with the amide. The CH2Cl2 is removed in vacuo, and the mixture is neutralized with 1N KH2PO4. The product is extracted into ethyl acetate and the organic phase is washed with water, with 1 N NaHCO3, and with brine. The solution is dried over Na2SO4, filtered and concentrated to an oil, which is chromatographed over silica gel, eluting with 5%–7% methanol (containing 1% of NH4OH) in CH2Cl2. Product-containing fractions are pooled, concentrated, dissolved in a small volume of ethanol, and acidified with 0.6 N HCl in dry ether. Concentration from this solvent mixture affords a gel-like material. This can be dissolved in ethanol and ethyl acetate, and concentrated to 1.65 g (3.3 mmol, 87%) an off-white solid. This solid is triturated with ethyl acetate to remove a pale yellow mother liquor, leaving hydrochloride 7 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.44 (s, 1H), 7.37 (m, 2H), 7.29 (m, 1H), 6.70 (m, 2H), 6.62 (m, 1H), 3.94 (m, 1H), 3.87 (m, 1H), 3.0–2.94 (m, 2H), 2.64 (m, 4H), 2.36 (m, 1H), 2.09 (m, 2H), 1.84 (s, 3H), 1.79 (m, 2H), 1.59 (m, 1H), 1.5–1.3 (m, 3H), 1.27 (d, J=7 Hz, 6H); IR (diffuse reflectance) 3343, 3254, 2958, 2937, 2866, 2497, 2442, 2377, 1660, 1628, 1598, 1553, 1460, 1116, cm−1. MS (EI) m/z (rel intensity) 458 (M+, 7), 415 (20), 230 (35), 202 (18), 201 (99), 200 (26), 159 (35), 157 (32), 133 (41), 129 (28), 117 (17). HRMS (ESI) calcd for C27H36N2O2F2+H1 459.2823, found 459.2837. Anal. Calcd for C27H36F2N2O2.HCl: C, 65.51; H, 7.53; N, 5.66; Cl, 7.16; F, 7.68. Found: C, 65.19; H, 7.70; N, 5.67. Found; Cl, 7.08.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH:9]([NH2:22])[CH2:10][N:11]([CH3:21])[C:12](=[O:20])[O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si](Cl)(C)C.Cl[C:29](OC1C=CC([N+]([O-])=O)=CC=1)=[O:30].Cl.[F:42][C:43]1[CH:44]=[C:45]([C@:49]([C@@H:57]2[CH2:62][CH2:61][CH2:60][NH:59][CH2:58]2)([OH:56])[CH2:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:46]=[CH:47][CH:48]=1>C(Cl)Cl.CCN(CC)CC>[F:42][C:43]1[CH:44]=[C:45]([C@:49]([C@@H:57]2[CH2:62][CH2:61][CH2:60][N:59]([C:29]([NH:22][CH:9]([CH2:8][C:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[CH2:10][N:11]([CH3:21])[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])=[O:30])[CH2:58]2)([OH:56])[CH2:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(CC(N)CC1(O)CCCCC1)C(=O)OCC[Si](C)(C)C
Reactant: COCCCC[C@@](O)(c1cccc(F)c1)[C@@H]1CCCNC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc(F)c1)[C@@H]1CCCN(C(=O)NC(CN(C)C(=O)OCC[Si](C)(C)C)CC2(O)CCCCC2)C1
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl 3-(1-hydroxycyclohexyl)-2-amino-propylmethylcarbamate (18.3 mg, 0.055 mmol) in CH2Cl2 (2 mL) was added Et3N (0.2 mL) and TMSCl (12 mg, 14 μL, 0.11 mmol). The resulting solution was stirred for 1 h and evaporated under vacuum. The residue was dissolved in CH2Cl2 (2 mL) and pyridine (0.05 mL) was added, followed by 4-nitrophenyl chloroformate (13.5 mg, 0.66 mmol). The solution was stirred for 30 min and (S)-1-(3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol hydrochloride (18 mg, 0.055 mmol). The resulting mixture was stirred for 10 min and evaporated. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (17.8 mg, 50%). MS m/z 652 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=1[O:23][CH3:24].OC1C=C(C)OC(=O)C=1C(=O)/C=C/C1C=CC(SC)=CC=1OC.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[SH:56].NCCS>>[OH:1][C:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:24])[S:56][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[N:49]=1
Reactant: Nc1ccccc1S
Reactant: COc1ccc(/C=C/C(=O)C2=C(O)CC(C)OC2=O)c(OC)c1OC
Agent: COc1cc(SC)ccc1/C=C/C(=O)c1c(O)cc(C)oc1=O
Agent: NCCS
Product: COc1ccc(C2CC(C3=C(O)CC(C)OC3=O)=Nc3ccccc3S2)c(OC)c1OC

Procedure:
Proceeding as in Example 2, but 4-hydroxy-6-methyl-3-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-5,6-dihydro-pyran-2-one substituted for 4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one and 2-amino-benzenethiol for 2-aminoethanethiol, provided 4-hydroxy-6-methyl-3-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-5,6-dihydro-pyran-2-one (Compound 56); MS M+ 456.2.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9](Cl)(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>O1CCCC1>[O:21]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCCCCCCCCCN1CCOCC1

Procedure:
A suspension of 2.30g (57.0 mmol) of sodium hydride (60% oil dispersion) in dry tetrahydrofuran (THF) and 5.0 g (57.0 mmol) of morpholine was refluxed under nitrogen for 30 minutes. After cooling, 12.56 g (57.0 mmol) of dodecanoyl chloride in THF was added dropwise, and the mixture was refluxed 30 minutes. Water was added, and the mixture was extracted with ethyl acetate (EtOAc). The combined organic phase was dried with MgSO4, concentrated in vacuo, and purified by flash chromatography (8:1 hexane/EtOAc) to give N-(oxododecyl)morpholine, as confirmed by NMR & IR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[CH2:7]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na]>CO>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:26][CH:25]=1
Reactant: COC(=O)CBr
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCOc1ccc(C(=O)OCC(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
Following the addition of 11.2 g (73 mMols) of bromoacetic acid methyl ester, a suspension of 20 g (67 mMols) of p-decyloxybenzoic acid, sodium salt, in 100 ml of methanol was heated for 3 hours and, after the addition of another 2 ml of bromoacetic acid methyl ester, for another 1.5 hours to boiling temperature. After the volatile constituents had been distilled off, the residue was extracted cold with methylene chloride, the solution was washed with water, concentrated by evaporation, the oily residue was taken up in petroleum ether, the solution was treated with active carbon and then reconcentrated by evaporation. p-decyloxybenzoyloxy acetic acid methyl ester melting at 30° to 32° C. was obtained in a yield of 15.8 g (68%). Purification by column chromatography (SiO2, Merck/methylene chloride:toluene=7:3) produced pure ester melting at 32.5° to 34° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:44]>C(Cl)Cl.CCOCC>[ClH:44].[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:22])[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=4)[C:4]=23)[CH2:24]1
Reactant: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cc1F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)cc1F
Yield: 63 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(3-fluoro-4-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.27 mmol) in DCM (3 mL) was treated with TFA (1 mL), followed by 1M HCl in ether according to the procedure described in Example 62, Step C, to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide hydrochloride (90 mg, 63% yield). 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.67-7.64 (m, 1H), 7.62-7.59 (m, 1H), 7.35 (s, 1H), 7.18-7.14 (m, 1H), 3.84 (s, 3H), 3.46-3.40 (m, 1H), 3.28-3.18 (m, 2H), 3.12-3.09 (m, 2H), 1.79-1.74 (m, 1H), 1.68-1.61 (m, 1H), 1.46-1.30 (m, 2H); LCMS (APCI+) m/z 462, 464 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[C:17]([Cl:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1c(Cl)ccc2c1O[C@@H](CN=[N+]=[N-])CC2
Temperature: 60 °C
Yield: 88.5 %

Procedure:
To a solution of ((2R)-7-chloro-8-o-tolylchroman-2-yl)methyl 4-methylbenzenesulfonate (0.8 g, 1.8 mmol) in DMSO (50 mL) was added sodium azide (1.2 g, 18.4 mmol) and the resulting mixture was heated at 60° C. overnight. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 0.5 g (88%) of (2R)-2-(azidomethyl)-7-chloro-8-o-tolylchroman as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1F
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(Nc3cc(Br)cnc3C#N)cc2)CC1

Procedure:
A solution of 5-bromo-3-fluoropicolinonitrile (1 g, 5 mmol), from EXAMPLE 49A, and 4-(4-methylpiperazin-1-yl)aniline (1.24 g, 6.5 mmol) in isopropanol (15 mL) was treated with triethylamine (0.76 mL, 7.5 mmol) was subjected to microwave irradiation (Biotage, Initiator) at 180° C. for 2 hours. The reaction mixture was concentrated and purified on silica gel with 2-25% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28]([O:30]CC)=[O:29])[CH2:10][C:11]1[S:12][C:13]([NH:16][C:17]([NH:19]C(=O)C2C=CC=CC=2)=[S:18])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:28]([OH:30])=[O:29])[CH2:10][C:11]1[S:12][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(NC(=S)NC(=O)c2ccccc2)s1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(NC(N)=S)s1)C(=O)O
Temperature: 25 °C

Procedure:
To a stirred solution of Ethyl N-(tert-butoxycarbonyl)-3-(5-(3-benzoylthioureido)-2-thienyl)-DL-alaninate (4.90 g, 10.2 mmol) in tetrahydrofuran (100 ml) was added 2N aqueous sodium hydroxide (12 ml, 24.0 mmol). The mixture was heated to reflux for 2.5 hours and cooled to room temperature. The mixture was placed in an ice bath and carefully neutralized to approximately pH7 with concentrated hydrochloric acid. The solvent was removed at reduced pressure to a volume of approximately 20-25 ml of a dark aqueous solution, and was extracted four times with ethyl acetate. The aqueous layer was adjusted to approximately pH4 with concentrated hydrochloric acid and concentrated at reduced pressure to give a dark red gummy solid. This material was taken up into ethyl acetate. All of the combined organic layers were dried over magnesium sulphate and the solvent was removed at reduced pressure to give a dark red gummy oil. This material was purified by column chromatography on silica gel eluting with 7.5:92.5:0.5 methanol:dichloromethane: acetic acid. The fractions containing the desired product were combined and concentrated at reduced pressure. The residue was redissolved in a small amount of methanol, diluted with toluene and reconcentrated at reduced pressure to azeotropically remove any remaining acetic acid. This process was repeated three times. N-(Tert-butoxycarbonyl)-3-(5-thioureido-2-thienyl)-DL-alanine. (2.33 g, 66%) was obtained as a yellow solid.
Reaction SMILES: C(O[C:4]1([C:15]([F:18])([F:17])[F:16])[CH:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5]1)C.FC(F)(F)[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)N[CH:22]=1.[NH:32]1CCCC[C:34]2C=CC=C[C:33]1=2>FC(F)(F)C(O)C(F)(F)F>[CH2:22]([CH:6]1[C:4]([C:15]([F:16])([F:17])[F:18])([OH:5])[N:32]2[C:10]3[CH:9]([CH2:14][CH2:13][CH2:12][C:11]=3[CH:34]=[CH:33]2)[CH2:8][CH2:7]1)[CH2:21][C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)CCCCN2
Reactant: FC(F)(F)c1c[nH]c2ccccc12
Reactant: CCOC1(C(F)(F)F)OC1CCc1ccccc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: OC1(C(F)(F)F)C(CCc2ccccc2)CCC2CCCc3ccn1c32
Yield: 36 %

Procedure:
A solution of 2-ethoxy-3-phenethyl-2-(trifluoromethyl)oxirane (300 mg, 1.15 mmol; prepared as described in RODRIGUES, I., et al., “1-Trifluoromethyl Epoxy Ethers. Effect of Hexafluoro-2-propanol on Reactions with Secondary Aromatic Amines: Synthesis of 3-Trifluoromethyl Indole Derivatives”, J. Org. Chem., 2001, pp 2098-2103, Vol. 66, Issue 6) and 2,3,4,5-tetrahydro-1H-benzo[b]azepine (170 mg, 1.15 mmol) in hexafluoroisopropanol was stirred at room temperature for 48 h. The solvent was evaporated to yield 2-phenethyl-1-(trifluoromethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indol-1-ol (150 mg, 36%) as a diastereomeric mixture, that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][NH2:20])=O)[N:12]=2)=[O:9])[CH:3]=1.C[N:22]([CH3:26])[C:23](=O)[CH3:24].[CH:27]1(N)CC1.C(O)(=O)C>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[N:22]([CH:23]4[CH2:27][CH2:24]4)[CH:26]=[N:20][N:19]=3)[N:12]=2)=[O:9])[CH:3]=1
Reactant: NNC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Reactant: NC1CC1
Reactant: CC(=O)N(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)n1)c1cc(Cl)ccn1
Temperature: 150 °C
Yield: 72 %

Procedure:
To a suspension of 4-chloro-N-(6-(hydrazinecarbonyl)pyridin-2-yl)picolinamide (1.00 g, 3.43 mmol) in toluene (0.20 M) was added a mixture of N,N-dimethylformamide.N,N-dimethylacetamide (1.14 mL, 8.56 mmol), cyclopropylamine (873 μL, 13.7 mmol), and acetic acid (194 μL, 3.43 mmol). The reaction mixture was heated to 150° C. for 30 minutes in a microwave reactor. The reaction product was concentrated under reduced pressure, and the residue was suspended in acetonitrile/diethyl ether (15 mL, 1:1 ratio), filtered, and the solid washed with acetonitrile/diethylether (2×10 mL). The filtrate was concentrated and the solid thus obtained was purified as above. The combined solids were dried under reduced pressure to afford 842 mg (72% yield) of 4-chloro-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)picolinamide as a white solid.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][C:38](O)=[O:39].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:34][O:35][CH2:36][CH2:37][C:38]([NH:18][S:15]([C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:6][CH:5]=2)[CH:10]=1)(=[O:17])=[O:16])=[O:39]
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Reactant: COCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(=O)NS(=O)(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45) (50 mg, 0.146 mmoles) in N,N-dimethylformamide (4.0 ml) was added diisopropylethylamine (85 μl, 0.480 mmoles) then a solution of 3-methoxypropionic acid (14 μl, 0.146 mmoles) in N,N-dimethylformamide (11.0 ml). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.160 mmoles) in N,N-dimethylformamide (1.0 ml) was added and the solution stirred at room temperature for 16 hours. The reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 65 as a white solid (42 mg). LC/MS System A: Rt=3.80 mins, m/z (ES−)=428 ((M−H) for C22H23NO6S).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:23].ClC1C=CC=C(C(OO)=[O:33])C=1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([CH2:15][S:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:33])[CH2:13][CH2:12][C:11]1=[O:23]
Reactant: COC(=O)CCCCCCC1C(=O)CCC1CSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COC(=O)CCCCCCC1C(=O)CCC1CS(=O)c1ccccc1
Yield: 85 %

Procedure:
In accordance with the process of Example 29, 2-oxo-5-phenylthiomethyl-cyclopentaneheptanoic acid methyl ester of Example 27 (890 mg; 2.58 m mol) and m-chloroperbenzoic acid having a purity of 85% (5.25 mg; 2.58 m mol) were used to obtain 800 mg of 5-benzenesulfinylmethyl-2-oxo-cyclopentaneheptanoic acid methyl ester as viscous oil.
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:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16]4[C:17](=[CH:18][O:19][C:20]=4[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:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[O:3]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: 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
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of wortmannin (100 mg) stirring in THF at -78° C. was added diisobutylaluminum hydride (0.4 mL of a 1.0M solution in toluene, 0.4 mmol). After 0.5 hour, the reaction was quenched with saturated aqueous NaHCO3. The mixture was then warmed to room temperature and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried (MgSO4). The crude material was purified by radial chromatography (SiO2, 4 mm, 9:1 EtOAc/Hexanes) to give a 70% yield of 17β-hydroxywortmannin as an off-white powder.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc2cccnc12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3cccnc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Quinoline-8-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=503.3.