Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:24]=1[CH:25]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:24]=1/[CH:25]=[CH:10]/[C:8]([C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=1[OH:11])=[O:9])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(O)c([N+](=O)[O-])c1
Yield: 42.6 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (500 mg, 2.56 mmol) and 2,4-dibenzyloxybenzaldehyde (900 mg, 2.83 mmol) were reacted according to the same procedure as Preparation 22 to give 540 mg (Yield 43%) of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:64][C:58]1[CH:59]=[CH:60][C:61]([F:63])=[CH:62][C:57]=1[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1
Reactant: O=C(O)c1cn(-c2ccccc2)cn1
Reactant: NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 49.6 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid (55 mg, 0.29 mmol) in DMF (5 mL) followed by HOBt (43 mg, 0.32 mmol) and EDCI (140 mg, 0.7 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (98.5 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by washing with ether to afford 63.5 mg (49.6% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 441.17. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 2H), 7.44 (t, 1H), 7.3 (m, 1H), 6.84 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.7 (bs, 2H), 3.5 (bs, 1H), 2.1 (t, 2H), 1.8 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1B(O)O)(=[O:20])[CH3:19].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1[C:13]1[N:14]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1)(=[O:20])[CH3:19]
Reactant: Cn1cc(Br)nc(Nc2cccc(N)c2)c1=O
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cccc(N)c3)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 219a (480 mg, 1.62 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (1.61 g, 4.05 mmol), Pd(dppf)Cl2 (134 mg, 0.162 mmol), potassium acetate (318 mg, 3.24 mmol), K3PO4 (706 mg, 3.24 mmol), acetonitrile (20 mL), and water (8 drops). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 20:1 ethyl acetate/methanol to afford 219b (354 mg, 38%) as a yellow solid. MS-ESI: [M+H]+ 568.3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Brc1ccc(OC2CCCCO2)cn1
Yield: 54.6 %

Procedure:
A mixture of 2-bromo-5-hydroxypyridine (1.0 g, 5.75 mmols), 3,4-dihydro-2H-pyran (0.80 mL, 8.77 mmols) and p-toluenesulfonic acid (110 mg, 0.578 mmol) was stirred overnight in dichloromethane (20 mL) at room temperature. The reaction liquid was diluted with chloroform, washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; ethyl acetate:hexane=1:20-1:10) to provide the title compound (0.81 g, 55%).
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[CH:6]=[C:7]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[S:8][CH:9]=1.[N+:16]([C:19]1[CH:23]=[N:22][NH:21][N:20]=1)([O-:18])=[O:17].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:15][C:10]1([C:7]2[S:8][CH:9]=[C:5]([CH2:4][N:21]3[N:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:23]=[N:22]3)[CH:6]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2cc(CCl)cs2)OCCO1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2cc(Cn3ncc([N+](=O)[O-])n3)cs2)OCCO1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(4-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane (230 mg, 1.05 mmol) in DMF (1.5 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (100 mg, 0.88 mmol) in DMF (1.5 mL) pre-treated for 30 min with DIPEA (0.30 mL, 1.75 mmol) and the reaction mixture was stirred for 16 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (2:1 hept-EA)=0.47. LC-MS-conditions 02: tR=0.98 min.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[N:27]=[N:28][NH:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15]C2CCCCO2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.O1CCOCC1.CC#N.C(Cl)Cl.[C:50](Cl)(=[O:55])[CH2:51][CH:52]([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>>[C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[NH:27][N:28]=[N:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15][C:50](=[O:55])[CH2:51][CH:52]([CH3:54])[CH3:53])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CC(=O)OC[C@](C)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reaction time: 0.17 h
Yield: 2.4 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (126 mg, 255 μmol) was combined with 4 M HCl in dioxane (191 μL, 765 μmol) in MeCN (0.7 mL, 10 mmol). The mixture was then concentrated under reduced pressure and the residue was purified by reverse phase chromatography. DCM (1 mL, 20 mmol) and isovaleryl chloride (39.9 mg, 306 μmol) were added, followed by DIPEA (133 μL, 765 μmol). The resulting mixture was stirred for 10 minutes. The solvent was evaporated and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (3 mg). MS m/z [M+H]+ calc'd for C27H32N4O5, 493.24. found 493.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@H:8]([O:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 79.2 %

Procedure:
To a solution of N-CBZ-cis-4-hydroxy-L-proline ethyl ester (6.4 g, 22 mmol) and anhydrous pyridine (5.3 mL, 5.2 g, 65 mmol) in CHCl3 (35 mL) was added p-toluenesulfonyl chloride (8.3 g, 44 mmol) in one portion. After stirring at room temperature for 7 days, the reaction was diluted with CH2Cl2 (100 mL) and pyridine removed by extraction with 10% HCl (4×13 mL). The organic layer was dried (MgSO4) and concentrated to a yellow oil which was purified by flash chromatography (silica gel, using 5:4 petroleum ether-ether) affording 7.8 g (80%) of 5 as colorless needles: mp 91°-92° C.; TLC Rf 0.15 (4:2 ethyl ether-petroleum ether); [α25D -26° (c 1.1, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.75 (app d, J=8.4 Hz, 2 H), 7.34-7.28 (m, 7 H), 5.18-5.04 (m, 3 H, PhCH2 and H-4), 4.52-4.41 (m, 1 H, H-2), 4.20-4.02 (m, 2 H, CO2CH2CH3), 3.78-3.62 (m, 1 H, H-5), 2.48-2.37 (m, 2 H, H-3), 2.45+2.44 (s, 3 H, PhCH3, two rotamers), 1.22+1.14 (t, J=7.1 Hz, 3 H, CO2CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 170.89, 170.57, 154.20, 153.89, 145.12, 145.09, 136.11, 133.88, 129.91, 129.85, 128.38, 128.32, 128.03, 127.98, 127.86, 127.77, 127.58, 78.62, 77.74, 67.21, 67.15, 61.47, 57.53, 57.30, 52.25, 51.99, 37.07, 35.98, 21.59, 13.92, 13.85; IR (CHCl3) 2995, 1745, 1700, 1415, 1360, 1175, 1120, 1050, 1020 cm1. Anal. Calcd for C22H25NO7S: C, 59.05; H, 5.63; N, 3.13. Found: C, 59.08; H, 5.54; N, 3.11.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8](SC)=[N:9][C:10]([C:14]([F:23])([F:22])[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=4)=[N:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>C(Cl)Cl.C1COCC1>[CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([NH:43][C:40]4[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=4)=[N:9][C:10]([C:14]([F:23])([F:22])[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=4)=[N:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C3CC3)ccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(C4CC4)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 7.7 %

Procedure:
To 7-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Step A (137 mg, 0.378 mmol) in DCM (5 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (139 mg, 0.567 mmol). The mixture was stirred for at 0° C. for 20 min, then DCM (15 mL) was added and the mixture was washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. To the residue was added 5-methyl-1H-pyrazol-3-amine (0.107 g, 1.01 mmol) in THF (5 mL) and the mixture was stirred at room temperature for 40 min and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% AcOH/CH3CN and solvent A=0.05% aq AcOH) to afford 7-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (12 mg, 8%) 1H NMR (300 MHz, DMSO-d6) δ 12.07-12.19 (m, 1H), 10.51-10.63 (m, 1H), 8.66 (s, 1H), 8.54 (d, J=8.7 Hz, 1H), 7.94-8.04 (m, 2H), 7.51 (s, 1H), 7.36 (d, J=8.7 Hz, 1H), 5.97 (s, 1H), 2.10-2.21 (m, 4H), 1.09 (dd, J=2.3, 8.1 Hz, 2H), 0.87-0.94 (m, 2H); LC-MS (ESI) m/z 411 (M+H)+
Reaction SMILES: [C:1]([C@H:3]([CH3:36])[CH2:4][NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])#[N:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:1]([C@H:3]([CH3:36])[CH2:4][NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])#[N:2]
Reactant: C[C@@H](C#N)CNC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: O
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C#N)CNC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.1 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-cyano-2-methyl-ethyl)-amide (32 mg, 0.06 mmol) was dissolved in dichloromethane (1.6 ml) and cooled in ice bath. Trifluoroacetic acid (0.8 ml) was slowly added and the reaction was stirred at room temperature for 2.5 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1 ml). Ethylenediamine (0.26 ml, 3.8 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 5 mg (20%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-cyano-2-methyl-ethyl)-amide.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[NH4+].C(OCC)(=O)C>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:29]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]2N
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC[C@H]2NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
(R)-Methyl 1-amino-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-02) (0.661 mmol, 1 eq) was dissolved in dichloromethane and DIPEA (2.5 eq) under a protecting gas atmosphere, and 2-chlorobenzoic acid chloride (1 eq) was added at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was diluted with 10% ammonium chloride solution and ethyl acetate, and the phases were separated. The organic phase was washed with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1) to yield (R)-methyl 1-(2-chlorobenzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-02). Yield: 74%
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:11]=1)=O)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C([O-])(O)=O.[Na+].C(OC(=O)[NH:50][C:51]1[CH:56]=[C:55]([CH3:57])[C:54]([C:58]([F:61])([F:60])[F:59])=[CH:53][C:52]=1[NH2:62])(C)(C)C>CN(C1C=CN=CC=1)C.C1COCC1.C1(C)C=CC=CC=1>[NH2:22][C:19]1[N:18]=[CH:17][C:16]([C:12]2[CH:11]=[C:10]([C:8]3[CH2:7][C:6](=[O:23])[NH:62][C:52]4[CH:53]=[C:54]([C:58]([F:59])([F:60])[F:61])[C:55]([CH3:57])=[CH:56][C:51]=4[N:50]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(N)nc2)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(N)nc3)c1)=N2
Temperature: 23 °C
Reaction time: 26.5 h

Procedure:
The title compound was prepared by the following sequence: 1.) To a solution of 3-[3-(6-Amino-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K25) (1.0 g, 3.2 mmol) and DMAP (8 mg, 0.064 mmol) in THF (6.4 mL) was added Boc2O (699 mg, 3.2 mmol) and mixture was stirred for 26.5 h at 23° C., poured onto sat. NaHCO3-solution (20 mL), extracted with EtOAc (twice 25 mL). The combined organic layers were washed with 0.5 M HCl (20 mL) and brine (20 mL), dried over Na2SO4. Removal of the solvent in vacuum left a light brown foam (1.273 g). 2.) Part of this material (206 mg, 0.5 mmol) and (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) were refluxed in toluene (3 mL) for 8 h, then the reaction mixture was cooled to 23° C., the precipitate was filtered off and washed with Et2O (10 mL) to give a yellow solid (70.8 mg). 3.) Part of the obtained material (63.7 mg, 0.101 mmol) was converted into the title compound by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (25.2 mg, 61%).
Reaction SMILES: [N+:1](=[C:3]([C:10](=[O:21])[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2].N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30].C(OCC)(=O)C>ClCCl.O>[CH2:32]([O:31][C:29]([O:19][C@@H:17]([C@H:16]1[C:15](=[O:20])[NH:14][C@@H:13]1[C@@H:11]([CH3:12])[C:10](=[O:21])[C:3](=[N+:1]=[N-:2])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH3:18])=[O:30])[CH:33]=[CH2:34]
Reactant: C=CCOC(=O)Cl
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCC=C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (14.6 g) in dichloromethane (100 ml) was added pyridine (6.05 ml) and allyl chloroformate (10.7 ml) at -78° C. The mixture was allowed to warm to ambient temperature and stirred for one day at the same temperature. The reaction mixture was poured into ethyl acetate (100 ml) and water (50 ml), washed in turn with water (50 ml) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting with a mixture of hexane and ethyl acetate (1:1 V/V) to give allyl (4R)-4-[(2R,3S)-3-{(1R)-1-allyloxycarbonyloxyethyl}-4-oxoazetidin-2-yl]-2-diazo-3-oxopentanoate (10 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][CH2:30][CH2:31][NH2:32])=[N:21]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][CH2:30][CH2:31][NH:32][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)=[O:13])=[N:21]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NCCNc1nsc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Reaction time: 4 h
Yield: 44.7 %

Procedure:
5-(Methoxycarbonyl)picolinic acid (390 mg, 2.2 mmol), was dissolved in anhydrous dichloromethane. Several drops of dimethylformamide were added, followed by oxalyl chloride (0.23 mL, 1.2 mmol). After 1.5 h at room temperature the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and added to a solution of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (300 mg, 1.6 mmol) in anhydrous dichloromethane with triethylamine (420 μL, 3.0 mmol). After 4 h, the reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography, on silica gel, eluting with a mixture of 2% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure. Trituration with boiling dichloromethane and methanol removed impurities and gave methyl 6-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinate (255 mg) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 9.11 (m, 1H), 8.55 (broad s, 1H), 8.40 (m, 1H), 8.24 (d, 1H), 7.68-7.76 (m, 2H), 7.42 (t, 1H), 7.32 (t, 1H), 3.98 (s, 3H), 3.88 ppm (m, 4H). MW=356 confirmed by LC-MS, tr=12.06 min (Method Y) MH+=357.
Reaction SMILES: [BrH:1].[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5](Cl)[N:4]=1>C(O)(=O)C>[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([Br:1])[N:4]=1
Reactant: Br
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A 30% solution of hydrogen bromide in acetic acid (10 ml) was added to 2-amino-6-chloro-3-nitropyridine (1.0 g) at room temperature and the mixture was heated at 100° C. After 24 hr, a 30% solution of hydrogen bromide in acetic acid (5 ml) was added. After 48 hr, the reaction mixture was cooled and concentrated. The residue was neutralized with 28% aqueous ammonia and extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was crystallized from isopropyl ether to give the objective compound (1.14 g) as yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C([O-])(O)=O.[Na+].C(N1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35])(OCC)=O.OP(O)(O)=O>CC(C)=O.O>[C:26]1(=[O:35])[N:1]([CH:2]2[C:13](=[O:14])[N:4]3[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]23)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Reaction time: 3 h

Procedure:
To a suspension of 181 g. of 7-amino-3-methyl-3-cephem-4-carboxylic acid (7-ADCA) in 1700 ml. of water, 142 g. of NaHCO3 were slowly added followed by a solution of 186 g. of N-carbethoxyphthalimide in 1 liter of acetone added dropwise over a 30 minute period. After stirring for 3 hrs. the solution was cooled in an ice-water bath and acidified to pH 2.1 by addition of 600 ml. of 42.5% of H3PO4. The resulting precipitate was filtered, washed with water, and vacuum dried to give 227 g. of a mixture of the starting material and the desired phthalimido compound. The mixture was separated by extraction with warm acetone and ethyl acetate, recovering 105 g. of 7-ADCA. The yield of the phthalimido compound was 114 g. A sample (1 g.) of product was crystallized from acetone (15 ml.); colorless crystals, m.p. 223°-225°; [α]D + 428.02° (MeCN); ir (nujol) 1810, 1785, 1740 and 1710 cm-1 ; nmr (CDCl3) δ 2.38 (s, 3, CH3), 3.0 and 3.75 (ABq, 2, J=14 Hz), 5.13 (d, 1, J=4.5 Hz), 5.71 (d, 1, J=4.5 Hz), and 7.82 (m, 4, ArH).