Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[C@@H:3]12[O:10][CH2:9][C@@H:7]([O:8]1)[CH:6]=[CH:5][C:4]2=[O:11].[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1>[C:12]([O:11][C@@:4]1([CH3:1])[CH:5]=[CH:6][C@H:7]2[CH2:9][O:10][C@@H:3]1[O:8]2)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)O[C@@]1(C)C=C[C@H]2CO[C@@H]1O2
Reaction time: 1 h

Procedure:
2.4 ml (1.5 mol) of methyl lithium was gradually added to 30 ml of a dry tetrahydrofuran solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose under starting at 0° C. under an inert atmosphere of nitrogen gas. Completion of the reaction was confirmed by thin layer chromatography, and then 0.25 ml of acetyl chloride was added to the reaction mixture. The ice bath was removed, and the reaction solution was returned to room temperature and further stirred for one hour. The solvent was distilled off under reduced pressure. To the residue, 200 ml of ethyl acetate was added. The mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:5) to obtain 0.29 g of the desired product (Compound No. 32). The NMR analytical data of this product are as follows.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+]>C(O)C.O>[CH2:11]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: OCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccccc1CO
Temperature: 50 °C
Yield: 77.7 %

Procedure:
A solution of 2-(hydroxymethyl)phenol (1.24 g, 10 mmol, Aldrich) and 1-bromobutane (1.18 ml, 11 mmol, Acros) in ethanol (5 ml) (total volume approximately 7 ml) was mixed in a flow reactor (Vapourtec R4, 30 ml PFA tubing, 110° C.) with a solution of aqueous NaOH (2N, 5 ml, 10 mmol) in water (2 ml). The reagents were each pumped at 0.5 ml/min), giving a reaction time of 30 minutes. After the 30 ml reactor, the solution passed through a second “cooling” reactor (5 ml) at 50° C. At the reactor output, a 250 psi back pressure regulator was used. After all starting solutions had been consumed, the system was purged with an additional 70 ml solvents (1:1, ethanol:water). The collected material was concentrated in vacuo. The residue was partitioned between water and EtOAc, and treated with saturated aqueous sodium bicarbonate solution. The aqueous phase was further extracted with EtOAc, and the combined organic extracts were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound (1.4 g); LCMS: (System 4) tRET=2.51 min, no MH+ detected.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32]>CN1C(=O)CCC1.CCOC(C)=O>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: O=C1CNCCN1
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 2 h

Procedure:
(rac)-6-Chloro-3-[1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate G, 100 mg, 0.303 mmol), KF (88 mg, 1.5 mmol), piperazin-2-one (91 mg, 0.91 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 2 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative UPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3 to remove the TFA salt. The filtrate was evaporated and the residue was triturated with pentane. The precipitate was filtered off and dried to afford the title compound as a white solid (tR 0.88 min (conditions 4), MH+=394, 1H-NMR in DMSO-d6: 8.10 (br. s, 1H); 7.95-7.87 (m, 2H); 7.65 (s, 1H); 7.51 (s, 1H); 7.54 (d, 1H); 7.49 (s, 1H); 7.22 (d, 1H); 4.79 (q, 1H); 3.95 (s, 4H); 3.87-3.78 (m, 1H); 3.67-3.55 (m, 2H); 3.22 (dd, 1H); 3.29-3.14 (m, 1H); 1.71 (d, 3H)).
Reaction SMILES: C(C1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)#N.[CH3:33][Mg]Br.[CH3:36][C:37]([OH:39])=O>C1COCC1>[C:37]([C:36]1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)(=[O:39])[CH3:33]
Reactant: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: C[Mg]Br
Reactant: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C(C)=O)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (137 mg) at 0° C. in THF (5 mL) was added methylmagnesium bromide (0.70 mL, 3M/ether). After stirring for 6 hour, 10% aqueous HOAc was added, the mixture was heated to 50° C. for 10 minutes then extracted with EtOAc. Purification (SiO2, 93/3/4 CH2Cl2 /MeOH/HOAc) gave 40 mg of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11].[H-].[Na+].[Cl:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1>CN(C=O)C>[ClH:14].[ClH:14].[CH:24]1([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[O:10])[C:2]3=[O:11])[CH2:18][CH2:19]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: ClCCN1CCN(CC2CCCCC2)CC1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C1C(=O)N(CCN2CCN(CC3CCCCC3)CC2)c2ccccc21
Temperature: 80 °C

Procedure:
1H-Indole-2,3-dione (2.4 g) in dry DMF (8 ml) at 0° C. was treated with sodium hydride (80% dispersion in mineral oil, 500 mg). The mixture was allowed to warm to room temperature and after 30 minutes 1-(2-chloroethyl)-4-(cyclohexylmethyl)piperazine (4 g) in dry DMF (8 ml) was added. The mixture was heated at 80° C. for 1.5 hours and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel and then treated with ethanolic HCl to give 1-[2-[4-(cyclohexylmethyl)-1-piperazinyl]ethyl]-1H-indole-2,3-dione dihydrochloride, m.p. 256°-258° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCO>[BrH:8].[Br:8][C:6]1[N:7]2[CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:1]=[C:2]2[C:3]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2N)CC1
Solvent: CCO
Product: Br
Product: CCOC(=O)c1cn2c(Br)cnc(N3CCNCC3)c2n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 112 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(3-amino-5-bromopyrazin-2-yl)piperazine-1-carboxylate (8.37 g, 0.0234 mol), ethyl 3-bromo-2-oxopropanoate (13.6 g, 0.070 mol) and EtOH (50 mL). The mixture was stirred at 90° C. for 6 h. Reaction progress was monitored by LC-MS. Work-up: the reaction mixture was filtered. The collected solid was washed with ethyl ether, to afford 5.7 g (56%) of ethyl 5-bromo-8-(piperazin-1-yl)imidazo[1,2-a]pyrazine-2-carboxylate hydrobromide. 1H NMR (300 MHz, DMSO-d6) δ: 8.43 (s, 1H), 7.73 (s, 1H), 4.37-4.32 (m, 6H), 3.16 (br, 4H), 1.34 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:38])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]([CH3:36])[C:19]1=[O:37])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:38])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]([CH3:36])[C:19]2=[O:37])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2cccc(F)c2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2cccc(F)c2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-J), the title compound was prepared as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:6]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>CN(C)C=O.ClCCl>[C:34]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[N:6]=1)(=[O:37])[CH2:35][CH3:36]
Reactant: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Reactant: CCC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (8.04 g) and pyridine (7.72 ml) in dry N,N-dimethylformamide (80 ml) was added slowly a solution of propionyl chloride (2.76 ml) in dichloromethane (2 ml) at a temperature below 5° C. After 30 minutes, the reaction mixture was poured into ice water (800 ml) and extracted with ethyl acetate (400 ml), and the extract was dried over magnesium sulfate. The solvent was distilled off and purified by column chromatography on silica gel to give 2-propionylamino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (8.9 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3c(F)cccc3F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Difluoro-benzoyl chloride (45 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H31F2N3O3+H: 520, observed: 520.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:19]=2[S:18]3)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>O>[N:38]1([CH2:37][CH2:36][O:27][C:25]2[CH:24]=[CH:23][C:20]3[N:21]4[CH:22]=[C:15]([C:12]5[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=5)[N:16]=[C:17]4[S:18][C:19]=3[CH:26]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
This product was prepared according to J. Med. Chem. 2009, 52, 7808-7816 with some modifications. A mixture of 2-amino-1,3-benzothiazol-6-ol (2.0 g, 12.18 mmol) and 2-bromo-4′-nitroacetophenone (2.97 g, 12.18 mmol) in IPA (40 ml) was heated to reflux for 24 h. The reaction mixture was then cooled to 0° C. and the resulting precipitate was filtrated and washed with IPA to afford 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol (65% c.y.). To a DMF (52 ml) solution of 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol was added potassium carbonate (2.94 g) and 4-(2-chloroethyl)morpholine hydrochloride (1.97 g). The reaction mixture was heated to 85° C. and stirred at the same temperature for 48 h. Then it was poured into water (100 ml), filtered and washed with water and ethyl ether to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole (86% c.y.). A mixture of 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole and ammonium chloride (0.77 g) in ethanol (50 ml) was heated to reflux, and then iron powder (3.0 g) was added. The mixture was refluxed for 5 h and then immediately filtered though Celite and washed with hot ethanol. The filtrate was concentrated, neutralized with saturated NaHCO3 solution and extracted with DCM. The organic solution was dried with Na2CO3 and the solvent was removed under reduced pressure to afford the desired product [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline (32% c.y.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>O1CCCC1>[ClH:1].[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Product: Cl
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 5.31 g (19.98 mmoles) of ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate dissolved in 40 ml of tetrahydrofuran was added 2.15 g (20.06 mmoles) of o-toluidine dissolved in 40 ml of tetrahydrofuran. The solution was stirred with exclusion of moisture at 60° C. for 18 hours. The yellow solid precipitate was filtered and washed with isopropyl ether; yield 7.13 g (95.7%). The product was recrystallized three times from methylene chloride: ethyl acetate, m.p. 191°-193.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CN1C(=O)CCC1.[CH3:13][C:14]([CH3:34])([CH3:33])[CH2:15][N:16]1[C:24]2[C:19](=[N:20][C:21]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[CH:22][CH:23]=2)[N:18]([CH3:31])[C:17]1=[O:32].CCN(C(C)C)C(C)C>CO>[CH3:13][C:14]([CH3:34])([CH3:33])[CH2:15][N:16]1[C:24]2[C:19](=[N:20][C:21]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26]3)=[CH:22][CH:23]=2)[N:18]([CH3:31])[C:17]1=[O:32]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CCCNC3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CCCN(S(C)(=O)=O)C3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask was added methanesulfonyl chloride (3.74 mg, 0.033 mmol), NMP (0.5 mL), then (18-2) (7.6 mg, 0.025 mmol), & DIPEA (40 μl, 0.229 mmol). The reaction mixture was stirred at room temperature for 3 hours, then diluted with MeOH & purified by reverse phase chromatography (5-95% CH3CN:0.1% TFA in H2O) to give 1-(2,2-Dimethylpropyl)-3-methyl-5-[1-(methylsulfonyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (19-1). HRMS (M+H)+: observed=381.1956, calculated=381.1955. 1H NMR (499 MHz, DMSO): δ 7.48 (d, J=7.9 Hz, 1H); 7.02 (d, J=7.9 Hz, 1H); 3.71-3.68 (m, 1H); 3.64-3.56 (m, 3H); 3.34 (s, 3H); 2.93-2.83 (m, 5H); 2.78-2.72 (m, 1H); 2.00-1.92 (m, 1H); 1.89-1.82 (m, 1H); 1.76-1.60 (m, 2H); 0.95 (s, 9H).
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.[CH3:36][C:37]1[N:42]=[CH:41][C:40](Br)=[CH:39][N: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:40]3[CH:39]=[N:38][C:37]([CH3:36])=[N:42][CH:41]=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: Cc1ncc(Br)cn1
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

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-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-methyl-5-bromopyrimidine following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.221 min, m/z=468.2; 1H NMR (CDCl3) 1.06 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.11-2.28 (m, 4H), 2.31-2.42 (m, 1H), 2.70 (s, 3H), 2.82 (m, 1H), 5.65 (m, 1H), 7.00 (d, 2H), 7.21-7.34 (m, 7H), 8.19 (s, 2H).
Reaction SMILES: [OH:1][P:2]([CH:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:4][C@@H:5]([CH3:23])[C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])=[O:3].C(O)C>O1CCOCC1.[OH-].[Li+].O>[OH:3][P:2]([CH:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([O:4][C@@H:5]([CH3:23])[C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])=[O:1]
Reactant: C[C@H](OP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](OP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The phenylmethyl ester product from part (a) (4.12 g., 6.9 mmole) is dissolved in dioxane (15 ml.) and 1N lithium hydroxide (15 ml.). Ethanol (several ml.) is added to solubilize the salts, and the reaction mixture is stirred overnight at room temperature under argon. The reaction mixture is diluted with water and washed with ether and ethyl acetate. This aqueous solution is acidified and extracted with ethyl acetate. This ethyl acetate solution is washed with brine, dried over sodium sulfate, and concentrated to give 1-[(S)-2-[[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]oxy]-1-oxopropyl]-L-proline as a viscous white oil.
Reaction SMILES: [OH:1][CH:2]([C:6]([O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH3:47])[N:44]=[C:43](S(C)(=O)=O)[N:42]=1>O>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([O:1][CH:2]([C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4])[N:42]=1
Reactant: COc1ccc(CCOC(c2ccccc2)(c2ccccc2)C(O)C(=O)O)cc1OC
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)nc(OC(C(=O)O)C(OCCc2ccc(OC)c(OC)c2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
1 g (2.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid was introduced into 10 ml of DMF, and 340 mg of NaH (50% suspension) were added. After the mixture had been stirred for 15 minutes, 526 mg of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off, the residue was purified by MPLC, and 655 mg (52%) of colorless powder were isolated after recrystallization from ether/n-hexane.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][N:19]([CH3:24])[CH2:20][CH:21]([NH2:23])[CH3:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH:21]([NH:23][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])[CH3:22]
Reactant: CC(N)CN(C)C
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccc(NC(C)CN(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.500 g, 2.08 mmol), N1,N1-dimethyl-1,2-propanediamine (0.636 g, 6.24 mmol), DIPEA (2.2 mL, 12.5 mmol) and DMF (12 mL) was stirred 4 hours at room temperature. The reaction was then concentrated in vacuo, the residue was dissolved in 2 N NaOH (30 mL) and extracted with CH2Cl2 (3×40 mL). The combined organic phases were washed with brine (10 mL) dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography (100% CH2Cl2 to 5% MeOH/CH2Cl2) to provide the title compound (0.621 g, 93%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.33 (d, J=6.4 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 6.91 (d, J=9.6 Hz, 1H), 3.79 (heptet, J=7.2 Hz, 1H), 3.45 (br d, J=5.2 Hz, 4H), 2.55 (dd, J=12.0 Hz, J=7.6 Hz, 1H), 2.39 (dd, J=12.4 Hz, J=5.8 Hz, 1H), 2.29 (s, 6H), 1.69 (br s, 1H), 1.31 (d, J=6.8 Hz, 2H), 1.22 (t, J=7.4 Hz, 6H). MS (ESI) (M+H)+=323.