Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].[F:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[N:24]=[C:23]([NH:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:22]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:42])[C@@H:38]([NH:40][CH3:41])[CH3:39])=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CN(C)C=O.CN1CCOCC1.ClC(OCC(C)C)=O.C(=O)([O-])O.[Na+]>[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([N:40]([C@@H:38]([CH3:39])[C:37]([NH:36][CH2:35][CH2:34][CH2:33][C:32]#[C:31][C:22]1[C:23]([NH:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[N:24][C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)=[N:20][CH:21]=1)=[O:42])[CH3:41])=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CN[C@@H](C)C(=O)NCCCC#Cc1cnc(Nc2cccc(F)c2)nc1NCCCOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Reaction time: 1 h

Procedure:
To a solution of 4-dimethylaminocrotonic acid hydrochloride (61 mg) in N,N-dimethylformamide (0.5 mL), N-methylmorpholine (135 μL) and isobutyl chloroformate (40 μL) were added under ice cooling, then (S)—N-(5-(2-((3-fluorophenyl)amino)-4-((3-methoxypropyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)-2-(methylamino)propanamide (J9) dihydrochloride (55 mg) was further added, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, saturated aqueous sodium hydrogencarbonate (10 drops) was added, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain (S,E)-4-(dimethylamino)-N-(1-((5-(2-((3-fluorophenyl)amino)-4-((3-methoxypropyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-N-methyl-2-butenamide (10-1, 45 mg).
Reaction SMILES: [CH:1]([O:4]C1C=CC=NC=1)([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].Br[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][N:45]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.C(OCC)(=O)C.O.C(O)C.C1(C)C=CC=CC=1.CS(C)=O>[CH:1]([O:4][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][N:45]=1)([CH3:3])[CH3:2]
Reactant: Brc1n[nH]c2ccccc12
Reactant: CC(C)Oc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Oc1n[nH]c2ccccc12
Temperature: 100 °C

Procedure:
5-isopropoxypyridine 2BIa (10 g, 0.046 mol), bis(pinacolato)diboron (14.1 g, 0.056 mol), potassium acetate (13.6 g, 0.14 mol) and PdCl2(dppf)2.CH2Cl2 (3.78 g, 0.0046 mol) were weight into a 2-necked 1 L flask equipped with a water condenser. DMSO (100 ml) was added and the mixture was purged with nitrogen for 15 min. The mixture was heated at 100° C. under nitrogen for 2 hr. After being cooled to r.t., water (100 ml), toluene (100 ml), ethanol (100 ml), potassium carbonate (32 g, 0.23 mol) and bromoindazole 3BI (22.4 g, 0.046 mol) were added. The mixture were purged with nitrogen for 10 min at r.t. and Pd(Ph3P)4 (5.35 g, 0.0046 mol) was added. The final mixture were heated at 100° C. for 2 hr and cooled to r.t. Water and ethyl acetate were added. Solids were filtered through Celite. Layers were separated and the separated organic layer was washed with water (×2). The combined aqueous layers were back extracted with ethyl acetate (×1). The combined organic layers were dried (MgSO4), filtered and solvents were removed in vacuum. Column purification [Hexanes-ethyl acetate=9:1 (v/v)] gave isopropoxyindazole 4BI (20 g, 80%) as yellow solid.
Reaction SMILES: N=C=N.[C:4]1([CH3:21])[CH:9]=[CH:8][C:7]([S:10]([NH:13][C@H:14]([C:18](O)=[O:19])[CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.[NH2:23][CH:24]([CH:32]([OH:59])[CH:33]([NH:41][C:42](=[O:58])[C@H:43]([CH:55]([CH3:57])[CH3:56])[NH:44][S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:51]1([CH3:54])[CH:52]=[CH:53][C:48]([S:45]([NH:44][C@H:43]([C:42]([NH:41][CH:33]([CH:32]([OH:59])[CH:24]([NH:23][C:18](=[O:19])[C@H:14]([CH:15]([CH3:17])[CH3:16])[NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:21])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:58])[CH:55]([CH3:57])[CH3:56])(=[O:46])=[O:47])=[CH:49][CH:50]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](C(=O)NC(Cc2ccccc2)C(O)C(N)Cc2ccccc2)C(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Agent: Cl
Agent: N=C=N
Product: Cc1ccc(S(=O)(=O)N[C@H](C(=O)NC(Cc2ccccc2)C(O)C(Cc2ccccc2)NC(=O)[C@@H](NS(=O)(=O)c2ccc(C)cc2)C(C)C)C(C)C)cc1

Procedure:
According to the carbodiimide coupling procedure of Example 55, N-(p-toluenesulfonyl)valine was coupled to the resultant compound of Example 112 to give the desired compound.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[Br:31]N1C(=O)CCC1=O>CN(C)C=O>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([Br:31])[C:19](=[O:23])[N:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(-c2ccccc2)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Br
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A mixture of 2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (11.8 mg, 0.0292 mmol) and N-bromosuccinimide (5.7 mg, 0.032 mmol) in N,N-dimethylformamide (0.2 mL) was shaken at 40° C. for 30 min. It was quenched and shaken with diluted aq. HCl (ca 0.1 M, 4 ml) then filtered to give the title compound as colourless solid (9.0 mg, 64% yield). LC-MS (m/z) 483.2 & 485.3 (MH+); tR=1.54. 1H NMR (T=+70° C., 500 MHz, DMSO-d6, DMSO-d5=2.50 ppm): 1.75 (overlapping s, 3H, Me), 1.72-1.93 (overlapping m, 5H), 2.07 (br. m, 1H), 2.2 (s, 3H, Me), 2.67 (m, 1H, CH of Cb), 4.93 (t, J=9.2 Hz, CH—N), 7.02 (dt, J(t)=8.3 Hz, J(d)=1.9 Hz, 1H), 7.13 (br. d, J=10.1 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.22 (br. m, 2H, Ph), 7.35 (q (unres. Dt), J(t)=7.6 Hz, J(d)=6.6 Hz, 1H), 7.49 (t, J=7.3 Hz, 1H, para-H of Ph), 7.55 (t, J=6.8 Hz, 2H, two meta-H of Ph), 8.68 (d, J=8.3 Hz, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH:9]([C:20](O)=[O:21])[NH:8][CH:7]=1)=[O:5])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[N:23]1([C:20]([CH:9]2[NH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)C1=CNC(C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C1=CNC(C(=O)N2CCCCC2)Cc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,2,3,6-tetrahydroazepino[4,5-b]indole-2,5-dicarboxylic acid 5-ethyl ester (45 mg, 0.15 mmol) in DCM (3 mL) was added CDl (27 mg, 1.1 equiv.). After stirring for 1 hour at 20° C., piperidine (23 μL, 1.5 equiv.) was added. The mixture was stirred overnight at 20° C. and a clear solution was obtained. Evaporation of solvent gave a crude product, which was purified by trituration with MeOH to afford the title compound (22 mg); 1H-NMR (CDCl3): δ 10.44 (1H, br s), 7.95 (1H, d), 7.38 (2H, d), 7.05-7.13 (2H, m), 6.69 (1H, d), 4.29 (2H, q), 3.98 (1H, dd), 3.65-3.73 (2H, m), 3.46 (1H, m), 3.31 (1H, m), 2.71 (1H, dd), 1.58-1.76 (6H, m), 1.36 (3H, t); MS (ES): 368 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[NH:24][C:23]4[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[C:16]2=[O:33])[C@H:11]([CH2:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:10]1.[CH3:44][C:45]([CH3:47])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:45]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[NH:24][C:23]4[C:25]([C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[C:16]2=[O:33])[C@H:11]([CH2:34][S:35]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:36])=[O:37])[CH2:10]1)([CH3:47])[CH3:44]
Reactant: N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 5.8 %

Procedure:
To a solution of Example 47 (67 mg, 0.13 mmol) in 1,2-dichloroethane (7.3 mL) was added acetone (0.38 mL, 5.2 mmol) and acetic acid (30 μL, 0.51 mmol). The resulting mixture was stirred for 20 min, then sodium triacetoxyborohydride (110 mg, 0.52 mmol) was added. After stirring for 2 h, the mixture was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The resulting clear, glassy solid was dissolved in CH3CN/H2O/TFA and lyophilized to provide the title compound (5.1 mg, 6%) as a white solid and mixture of diastereomers: ESI MS m/z 563 [C28H33F3N4O3S+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:19][NH:20][C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B-](F)(F)(F)[F:27].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(N(C)C)=O.CO>[F:27][C:13]1[C:14]2[NH:20][N:19]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[C:15]=2[CH:16]=[N:17][C:12]=1[NH:11][C:10]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:25]
Reactant: CC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N-(6-(3-(1-Phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (Example 47; 75 mg, 0.222 mmol) was dissolved in DMA (0.5 mL) and methanol (0.5 mL), charged with powdered Selectfluor® (86 mg, 0.244 mmol), and stirred at room temperature overnight. The reaction was then heated to 65° C. for 2 h. The resulting crude residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)—N-(7-fluoro-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. for C17H17FN6O2 [M+1]+ 357. found 357. 1H NMR (500 MHz, DMSO-d6) δ 13.83 (s, 1H) 11.15 (s, 1H), 10.79 (s, 1H), 9.86 (s, 1H), 8.28 (d, J=7.3, 1H) 7.34 (m, 4H), 7.34 (m, 1H), 4.88 (m, 1H), 2.20 (S, 3H), 1.43 (d, J=6.9, 3H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10]CC)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19]O)[CH2:16][O:15]1.[H-].[Na+]>C1COCC1.[Cl-].[Na+].O>[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19][O:1][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:16][O:15]1
Reactant: CCOC(=O)c1cccc(O)n1
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)n2)O1
Temperature: 25 °C
Yield: 74 %

Procedure:
Ethyl 6-hydroxypicolinate (500 mg, 2.7 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (1.11 mL, 3.0 eq) and NaH (60% dispersion in mineral oil, 385 mg, 3.3 eq) in THF was refluxed 18 hours. The reaction mixture was cooled to room temperature, acidified to pH=4, added to brine and extracted with ethyl acetate. The organic layer was dried, concentrated and recrystallized from pentane/ethylacetate to obtain (R)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)picolinic acid (500 mg, 74% yield).
Reaction SMILES: [I-].[C:2]1([CH:8]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:29])[C@@H:19]([NH:20][C:21](=[O:28])[CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[CH2:30][P+:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.O>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:29])[N:17]2[C:12]([C:10]([O:9][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:11])=[C:13]([CH:30]=[P:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:14][S:15][C@H:16]12)=[O:28]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Yield: 79.4 %

Procedure:
A solution of [4-diphenylmethoxycarbonyl-7β-(2-thienylacetamido)ceph-3-em-3-ylmethyl] triphenylphosphonium iodide (25 g.) in acetone (300 ml.) with water (40 ml.) was cooled to 0° and taken to pH 11 with 2N-sodium hydroxide. The mixture, containing a precipitated yellow solid, was diluted with acetone (200 ml.) and water (50 ml.), and filtered. The collected solid was washed with acetone and ether, and dried in vacuo to give diphenylmethyl 7β-(2-thienylacetamido)-3-(triphenylphosphoranylidenemethyl)ceph-3-em-4-carboxylate (17 g., 78.5%) as a yellow crystalline solid, m.p. 133°-138° (Decomp), [α]D - 35° (CHCl3), λmax (CHCl3) 388 nm. (ε 18,500), 273 nm (ε6,240) and 267 nm (ε6,940), νmax (CHBr3) 3360 (NH), 1746 (β-lactam), 1670 (CO2R), 1642 and 1500 (CONH), and 1438 (P-C aryl) cm-1 ; τ(CDCl3) 4.82 (C(7) --H, dd, J 4.5, 9Hz), 4.95 (C(6) --H,d, J 4.5 Hz), 7.11 and 7.55 (C(2) --CH2, two dd. J 14 Hz., JP-H 1-2 Hz) and 4.5 ##STR34## [Found: C, 66.6; H, 4.7, N, 2.9; P, 3.9; S, 7.8. C45H37N2O4S2P (764.8) requires C, 70.6; H, 4.8; N, 3.6; P, 4.0; S, 8.4%[.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1
Yield: 73.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step A using methyl 3-aminobenzoate (16 g, 105.9 mmol) in DCM (150 mL) and 2,5-difluorobenzene-1-sulfonyl chloride (24.7 g, 116.5 mmol) the title compound was obtained (25.6 g, 73.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06-11.13 (br, 1H), 7.42-7.52 (m, 2H), 7.52-7.77 (m, 4H), 7.78-7.80 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]2[O:20][C:19]3[C:21]([NH:25][CH2:26][CH2:27]Cl)=[CH:22][CH:23]=[CH:24][C:18]=3[CH2:17][S:16](=[O:30])(=[O:29])[C:15]=2[CH:31]=1)=[O:10]>CN(C)C=O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]2[O:20][C:19]3[C:21]([NH:25][CH2:26][CH2:27][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:22][CH:23]=[CH:24][C:18]=3[CH2:17][S:16](=[O:29])(=[O:30])[C:15]=2[CH:31]=1)=[O:10]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(NCCCl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(NCCN3CCOCC3)c1O2
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Morpholine (0.2 mL, 2.52 mmol) was added to a solution of Example 160 (0.5 g, 1.26 mmol) in dry dimethylformamide (10 mL) and the reaction mixture was stirred at 110° C. for 3 h. It was concentrated, treated with water and the solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.5 g, (88.80%); 1H NMR (DMSO-d6): δ 2.35-2.45 (m, 4H, 2CH2), 2.60-2.70 (m, 4H, 2CH2), 2.80 (s, 3H, CH3), 3.10-3.20 (m, 2H, CH2), 3.55-3.60 (m, 2H, CH2), 3.90 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 6.70-6.85 (m, 2H, Ar), 7.20 (t, 1H, Ar), 8.10 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (EI+) 446 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29]I)[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][N:31]=[N+:32]=[N-:33])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](CI)[C@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](CN=[N+]=[N-])[C@H]1OC(C)=O
Temperature: 85 °C
Reaction time: 24 h

Procedure:
A suspension of 11 (8.0 g) and sodium azide (2.0 g) in DMF (100 ml) is heated with stirring for 24 hours at 85° C. (bath temperature). The solvent is evaporated in vacuo and the residue is partitioned between chloroform and water. The organic layer is separated and washed with water, dried, and evaporated to a thick syrup (7.2 g, 98%): [α]D27 +107±0.5° (C 1.0, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CN(C)C=O.I[CH:15]([CH3:17])[CH3:16]>C(=O)([O-])O.[K+].O>[CH:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1O
Reactant: CC(C)I
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1ccccc1O

Procedure:
Into a 100 mL flask purged with nitrogen were added 12 g (109.92 mmol) of o-aminophenol and 60 mL of dimethylformamide (DMF), and the resultant mixture was stirred at room temperature and dissolved. Then, the obtained solution was mixed with 22.4 g (132 mmol) of 2-iodopropane such (molar ratio of 2-iodopropane to o-aminophenol: 1.2), and further with 11.4 g (114 mmol) of potassium hydrogencarbonate (KHCO3) as a catalyst, and the resultant mixture was stirred at room temperature for 5 h. After conducting the reaction for 5 h, 50 mL of water was added to the reaction solution to terminate the reaction.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]>C1COCC1>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:29])[F:28])[O:1][N:2]=[C:3]([C:4]3[C:12]4[N:8]([CH:9]=[CH:10][CH:11]=4)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=3)[CH2:26]2)[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]
Reactant: CCOC(=O)c1ccc(/C=N/O)c2cccn12
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2cccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A solution of crude (E)-ethyl 8-((hydroxyimino)methyl)indolizine-5-carboxylate (1.15 mmol) in THF (20 mL) was added slowly to a stirred solution of DIB (528 mg, 1.64 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (452 mg, 1.64 mmol) in THF (10 mL) at rt. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then Combiflash to give ethyl 8-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (130 mg; yield 22% over 2 steps). MS: m/z=506.7 (M+1, ESI+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]2[C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O[C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40])=O>CN(C=O)C>[F:36][C:35]1[C:30]([O:14][C:13]([C:6]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=2)=[O:15])=[C:31]([F:40])[C:32]([F:39])=[C:33]([F:38])[C:34]=1[F:37]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])cn1CC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc([N+](=O)[O-])cn1CC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a solution of 1-cyclopropylmethyl-4-nitro-1H-pyrrole-2-carboxylic acid (8.07 g, 38.39 mmol) in anhydrous DMF (120 ml) in the presence of N,N-diisopropylethyl-amine (7.69 ml) was added dropwise pentafluorophenyl trifluoroacetate (7.59 ml, 44.15 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 5 h. After removal of solvent, the crude product was purified by chromatography on silica gel eluted by toluene-ethyl acetate (50:1) to give compound 278 (14.28 g, 98%) as a white powder. H1-NMR (DMSO-d6) 8.58 (d, 1H), 7.84 (d, 1H), 4.22 (d, 2H), 1.32−1.06 (m, 1H), 0.55–0.51 (m, 2H), 0.45−0.42 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1(O)[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1.Cl>>[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: Cc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1C
Agent: Cl
Product: Cc1cccc(C2=CN(Cc3ccccc3)CCC2)c1C
Yield: 12 %

Procedure:
A mixture of 7 parts of 3-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride and 200 parts of a hydrochloric acid solution 6N was stirred and refluxed overnight. The reaction mixture was evaporated. Water was added and the base was liberated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 0.7 parts (12%) of 5-(2,3-dimethylphenyl)-1,2,3,4-tetrahydro-1-(phenylmethyl)pyridine as a residue (intermediate 45). The second fraction was collected and the eluent was evaporated, yielding 5.3 parts (91%) of 5-(2,3-dimethylphenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine as a residue (intermediate 46).
Reaction SMILES: [CH3:1][C:2]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: O=CCCl
Reactant: CSc1cccc(N)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1cccc(NCC=O)c1C
Temperature: 150 °C

Procedure:
2-Methyl-3-methylthioaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-3-methylthioanilino)acetaldehyde.