Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)(O)C1C=CC(F)=NC=1.O1CCN(CCOC2C=CC(C3C=CC(CC#N)=NC=3)=CC=2)CC1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[CH:52][C:53]([CH2:56][C:57](OC)=[O:58])=[N:54][CH:55]=3)=[CH:46][CH:45]=2)[CH2:37][CH2:36]1.FC1N=CC(C2C=CC(OCCN3CCOCC3)=CC=2)=CC=1.[CH2:83]([NH2:90])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>>[O:35]1[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][O:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[CH:51]=[CH:52][C:53]([CH2:56][C:57]([NH:90][CH2:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)=[O:58])=[N:54][CH:55]=3)=[CH:48][CH:49]=2)[CH2:39][CH2:40]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: OB(O)c1ccc(F)nc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
In another aspect the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with methane sulfonic acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35]1>>[CH:34]1([N:37]2[CH2:42][CH2:41][N:40]([C:30]([C:26]3[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])=[O:32])[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: C1CN(C2CC2)CCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCN(C2CC2)CC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 1-cyclopropyl-piperazine to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>O1CCCC1>[C:40]([NH:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:25])=[CH:5][N:6]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12

Procedure:
On treating 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g) with benzoyl chloride (1.11 cc) in dry tetrahydrofuran (55 cc) in the presence of triethylamine (1.23 cc), using the working method of Example 1 (B), 3-(2-benzamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (1.8 g) is obtained in the form of cream-coloured crystals.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](=[S:17])(OCC)[S-:13].[K+].Cl>CN(C=O)C.O>[N+:9]([C:6]1[CH:7]=[CH:8][C:2]2[S:13][C:12]([SH:17])=[N:4][C:3]=2[CH:5]=1)([O-:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2sc(S)nc2c1
Temperature: 110 °C
Yield: 93.5 %

Procedure:
A mixture of 2-fluoro-5-nitro aniline (11, 1.00 g, 6.40 mmol) and potassium O-ethyl dithiocarbonate (1.53 g, 9.60 mmol) in DMF (15 mL) was heated overnight at 110-110° C. under N2. After cooling, the reaction mixture was diluted with water and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to yield compound 12 (1.27 g, 94%).
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C)(=O)=O.O[C:14]1([C:20]2[O:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[C:14]1([C:20]2[O:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: OC1(C2=COc3ccccc3O2)CCCCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1=C(C2=COc3ccccc3O2)CCCC1

Procedure:
Under an inert atmosphere, 14 ml of triethylamine and 3.85 ml of mesyl chloride are added slowly to a solution of 10 ml of 2-(1-hydroxy-1-cyclohexyl)-1,4-benzodioxin in 75 ml of dichloromethane at 0° C. The mixture is brought to reflux after 15 minutes for 1.5 hours. After hydrolysis, an extraction with dichloromethane is carried out, and the organic phase is then dried over magnesium sulfate and concentrated under vacuum. The diene is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 7:3) in the form of an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>O>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: CSc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: O=CN1CCNCC1
Solvent: O
Product: CSc1ncnc2c(N3CCOCC3)nc(N3CCN(C=O)CC3)nc12

Procedure:
10.4 gm (0.035 mol) of 2-chloro-8-methylthio-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p. 179°-180° C.) were heated with 28.5 gm (0.25 mol) of N-formyl-piperazine at about 100° C. for 30 minutes. The resulting solution was taken up in about 300 ml of water, whereby the reaction product was obtained as yellowish precipitate. The precipitate was suction-filtered off, washed with water and dried at 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N#N.[H-].[Na+].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
A 500 mL 3-neck round-bottom flask was charged with 6-bromo-1H-indole (5.95 g, 30.4 mmol) and THF (60 ml) to give a deep red solution. The flask was fitted with a N2 sweep, then cooled in an ice bath until an internal temperature of 2 to 5° C. was reached. At this time, sodium hydride (1.457 g, 36.4 mmol) was added portion-wise over 2 to 3 minutes such that the internal temperature was maintained below 10° C. The resulting mixture was stirred at this temperature for 20 minutes before triisopropylsilyl chloride (8.12 ml, 37.9 mmol) was added over 1 min. The cooling bath was removed, and the mixture was stirred for 15 min at room temperature. The volatiles were evaporated in vacuo, and the residue was taken up in saturated aq. sodium bicarbonate solution (150 mL). The mixture was extracted with DCM (2×250 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 10% EtOAc/Heptane) to give 6-bromo-1-(triisopropylsilyl)-1H-indole (7.33 g, 20.80 mmol, 68.5% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ=8.22 (td, J=0.8, 1.5 Hz, 1 H), 7.85-7.70 (m, 2 H), 7.58 (d, J=3.1 Hz, 1 H), 6.78 (dd, J=1.0, 3.1 Hz, 1 H), 1.84-1.65 (m, 3 H), 1.17 (d, J=7.5 Hz, 18 H).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of hydroxylamine hydrochloride (7.0 mg, 0.099 mmol) in methanol (0.2 mL) and 2,6-lutidine (0.2 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 61, 31 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (30 mg, 93.7%) was a white foam: [α]23589=−23.24° (c=0.37, chloroform); EI-HRMS m/e calcd for C20H22Cl2N4O4S (M+H)+ 485.0812. found 485.0822.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a three-necked, 500 mL, round-bottomed flask fitted with a nitrogen inlet, mechanical stirring apparatus, and septum was added D-allo-threonine (24.98 g, 210 mmol) followed by anhydrous DMSO (250 mL) and potassium carbonate (63.7 g, 460 mmol). This mixture was stirred under nitrogen at room temperature for a period of 30 min. To this mixture was then added 2-chloro-4-fluoro-3-methylbenzonitrile (35.51 g, 210 mmol) followed by heating of the reaction mixture to 70° C. in an oil bath for a period of 48 hs. The reaction was then allowed to cool to room temperature followed by subsequent cooling to 0° C. and a 5% citric acid/water solution (1.5 Liters) was slowly added followed by careful addition of solid citric acid until evolution of gas was no longer observed. This solution was then extracted with EtOAc (5×1 L). The combined organic extracts were then dried over Na2SO4 and decanted away from the drying agent. The solvent was then removed under reduced pressure using rotary evaporation to reveal a red oil that was purified by silica gel chromatography by first eluting with hexanes/EtOAc, 1/1 (2 L) followed by methanol/EtOAc 1/7 (5 L) to afford of (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid as a light red oil/solid (27.05 g, 48%). 1H NMR (500 MHz, CD3OD, δ in ppm) 7.42 (d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.17 (m, 1H), 2.32 (s, 3H), 1.35 (d, J=6.6 Hz, 3H); 13C NMR (125.6 MHz, CD3OD) δ 174.2, 151.9, 137.16, 134.0, 122.6, 119.1, 110.1, 101.2, 69.1, 63.2, 20.0, 14.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[I:19]N1C(=O)CCC1=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:19])[CH:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1

Procedure:
trans-[4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (18.00 g, 67.74 mmol) and N-iodosuccinimide (19.81 g, 88.06 mmol) in anhydrous DMF (360 mL) were stirred at 60° C. under N2 for 6 h. The reaction was diluted with DCM (˜600 mL), washed with water and brine, dried over anhydrous Na2SO4 and then concentrated in vacuo. The crude material was purified by a silica gel flash chromatography (eluted with 1:2 EtOAc/DCM to 1:1 EtOAc/DCM) to obtain the desired product as a pale yellow solid; By 1H NMR analysis, the product was contaminated with 0.35 eq. of NIS-impurity. The product was carried onto the next reaction without further purification; MS (ES+): m/z 391.92 (100) [MH+], 393.88 (50) [MH+2], 394.89 (10) [MH+3]; tR (polar-5 min/openlynx) 2.79 min.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH2:19][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:15]1=[O:29].C1C[O:33]CC1>CCCCCC>[OH:33][CH:16]1[CH2:17][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][N:14]([CH3:13])[C:15]1=[O:29]
Reactant: C1CCOC1
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of 118 ul (0.833 mmol) diisopropylamine in 3 ml THF were added 520 ul (0.833 mmol) of a 1.6M n-BuLi solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 150 mg (0.641 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A.9, step 1) in 1.5 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. 517 mg (1.282 mmol) (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) were added portionwise at −70° C. The mixture was stirred at −70° C. for 1 hour and then allowed to warm to 0° C. After 1 hour at 0° C., the mixture was quenched with 2.5 ml of a saturated solution of sodium sulfite. Water and ethyl acetate were added. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 82 mg (51%) of the title compound as a light brown oil. MS (m/e): 251.1 (MH+).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:37]1[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)cc[nH]1
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 1. LC-MS Method 1 tR=1.23 min, m/z=389, 447 (M+1); 1H NMR (CD3OD) 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:1]([C:2]3[C:7]4[N:8]=[C:9]([CH3:11])[O:10][C:6]=4[C:5]([C:12]#[N:13])=[CH:4][CH:3]=3)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: Cc1nc2c(N)ccc(C#N)c2o1
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: Cc1nc2c(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc(C#N)c2o1

Procedure:
The title compound was prepared from 11C by procedures analogous to those described in Example 2 (2E to 2F) to give the product as a white foam. HPLC: 99% pure at 10.55 min (retention time) (CHIRALPAK® OD column 4.6×250 mm; 25% isopropanol in hexane over 30 min, 1 mL/min, monitoring at 220 nm); MS (ES) m/z 313 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13]([OH:15])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13]([Cl:17])=[O:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(C(=O)O)c2cc(F)ccc2n1
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)c2cc(F)ccc2n1

Procedure:
A solution of 6-fluoro-2-methylquinoline-4-carboxylic acid (500 mg) and PCl5 (500 mg) in dichloromethane (10 mL) was refluxed for half an hour. Then dichloromethane and POCl3 were removed under reduced pressure to give 6-fluoro-2-methylquinoline-4-carbonyl chloride.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17](Cl)=[O:18]>[OH-].[Na+]>[O:18]=[C:17]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:16]1
Reactant: O=C(O)[C@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 18.5 %

Procedure:
To a 0° C. solution of N-benzylserine (19.15 g, 105.7 mmol) in 2 N aq. NaOH (100 mL) was added chloroacetyl chloride (10.2 mL, 126.4 mmol) dropwise, and the solution was stirred for 45 min. To the solution was added 30% aq. NaOH (40 mL) dropwise, and the reaction was stirred for 1 h, and then stirred and warmed to room temperature for 72 h. The reaction was adjusted to pH 1 and extracted with three portions of EtOAc. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was washed with EtOAc/hexane to give (3S)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (4.61 g, 19% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12](F)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[OH:16])=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cn1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(C(O)c2ccc(Cl)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
A solution of 5-chloro-2-(4-fluorobenzoyl)pyridine (3.0 g) and sodium azide (0.84 g) in DMSO (60 ml) was stirred for 20 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (3.19 g) in. THF (60 ml) was added dropwise to a suspension of aluminum lithium hydride (0.97 g) in THF (10 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and water (0.97 ml), 15% aqueous solution of sodium hydroxide (0.97 ml) and water (2.9 ml) were sequentially and slowly added dropwise to the solution. The mixture was stirred at room temperature for 18 hours, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give (4-aminophenyl)(5-chloropyridin-2-yl)methanol (0.90 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:5].[H][H]>O1CCCC1.C(O)CC>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:3]=1[C:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:5]
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCCO
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N)ccc1Cl
Temperature: 25 °C
Yield: 94.6 %

Procedure:
In a stirred autoclave, 0.1 g of a catalyst prepared according to Example H1 is added to a solution of 10 g of allyl 2-(2-chloro-5-nitrobenzoyloxy)-2-methylpropionate in 80 ml of tetrahydrofuran and 20 ml of n-propanol, 6 mg (0.1 mol %) of FeCl2 4H2O are added in addition and the mixture is hydrogenated for 7 hours at a temperature of 140° C. and at a hydrogen pressure of 20 bar. After cooling to room temperature and flushing the stirred autoclave with nitrogen, the catalyst is filtered off. 117.3 g are obtained of a solution having a content of 7.26% of allyl 2-(2-chloro-5-aminobenzoyloxy)-2-methylpropionate (yield: 94.6% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:12]2[CH:17]=[CH:16][C:15]([C:2]3[CH:3]=[C:4]4[CH:10]=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[C:14]([F:21])[CH:13]=2)=[C:14]([F:21])[CH:13]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: OB(O)c1ccc(Br)cc1F
Product: Fc1cc(Br)ccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1
Temperature: 90 °C

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate HF heating at 90° Celsius for 16 hours and using 5-bromo-1H-pyrrolo[2,3-b]pyridine and 4-bromo-2-fluorobenzeneboronic acid. MS (ESI): mass calcd. for C19H11BrF2N2, 384.01; m/z found, 385.0, 387.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 12.29 (s, 1H), 8.47 (s, 2H), 7.60-7.50 (m, 2H), 7.50-7.34 (m, 5H), 6.73 (s, 1H).