Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])[CH:15]=1.C([O-])(O)=O.[Na+]>CN1CCCC1=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[CH:21]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(-c2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c([N+](=O)[O-])c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of 4-Fluoro-3-nitroacetophenone (5 g, 27.3 mmol) and 3-(3-pyridyl)aniline (4.62 g, 27.2 mmol) in dry 1-methyl-2-pyrrolidone (10 ml) is stirred at 40-50° C. overnight. The resulting solid reaction mixture is suspended in ice water (50 ml) and made alkaline by addition of 1 M NaHCO3. The product is filtered off, washed with water and dried to yield 7.68 g 4-acetyl-2-nitro-N-(3-(3-pyridyl)phenyl)aniline (85%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@H:7]2[C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][OH:17])[O:8]2)=[CH:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[CH2:26](Br)[C:27]#[CH:28].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C@H:7]2[C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][OH:17])[O:8]2)=[CH:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:28][C:27]#[CH:26])=[CH:21][CH:20]=1
Reactant: C#CCBr
Reactant: OC[C@H]1O[C@@H](c2cc(Cc3ccc(O)cc3)c(Cl)s2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)sc2Cl)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 37.5 %

Procedure:
To a solution of phenol 29 (124 mg, 0.320 mmol) in acetone (10 mL) were added propargyl bromide (80 wt % in toluene, 1.7 g, 11.2 mmol) and Cs2CO3 (1.5 g, 11.2 mmol) at room temperature. The mixture was stirred at 50° C. for 20 hours. The reaction mixture was cooled to room temperature and filtered off through celite. The filtrate was concentrated in vacuo. The residue was purified by prep HPLC (C18) to provide the title compound 30 (51 mg, 38%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCC1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To an ice-cooled solution of 4.13 g (20.7 mmol) 3-hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester and 244 mg (2 mmol) DMAP in 50 ml pyridine was added 3.06 g (30 mmol) acetic anhydride. The mixture was stirred for 30 min at 0° C., then for additional 60 min at room temperature. The mixture was poured on ice and extracted twice with ether. The combined organic layers were evaporated in vacuo, dissolved in ether, washed with sat. CuSO4, water and brine and dried over MgSO4. Evaporation and bulb-to-bulb distillation gave 4.82 g (97%) 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester as a colorless oil, b.p. 105° C. (0.2 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)[C:9]2[C:10]([C:15](O)=[O:16])=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:14])[CH:13]=3)[C:15](=[O:16])[N:18]2[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2cn(C)nc2C(=O)O)cn(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2C(=O)c3nn(C)cc3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-methyl-1H-pyrazole-3-carboxylic acid (Step 13.2). tR: 3.44 min (HPLC 1); tR: 0.77 min (LC-MS 2); ESI-MS: 369 [M+H]+ (LC-MS 2); Rf=0.46 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (s, 3H) 3.37 (s, 3H) 3.95 (s, 3H) 6.15 (s, 1H) 7.22 (d, J=8.6 Hz, 2H) 7.38 (d, J=8.6 Hz, 2H) 7.40 (m, 1H) 7.81 (m, 1H) 7.86 (s, 1H).
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](=O)[CH2:21][CH2:22][CH:23]2[CH2:26][C:27]#[N:28])=[CH:18][CH:17]=1>C(O)(C)C>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH2:22][CH:23]2[CH2:26][C:27]#[N:28])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)C(CC#N)CCC2=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: COc1ccc2c(c1)C(CC#N)CC=C2
Yield: 85 %

Procedure:
Aluminium isopropoxide (2.05 g, 10.0 mmol) is added to a solution of the compound obtained in Step B (680 mg, 3.15 mmol) in isopropanol (15 mL) at ambient temperature. The reaction mixture is refluxed. When the reagents have been completely consumed, a few crystals of p-toluenesulphonic acid monohydrate are added and a Dean-Stark apparatus is mounted on top of the flask. The mixture is again refluxed for 1 hour, during which the isopropanol is gradually replaced with toluene by means of the Dean-Stark apparatus. A 1N HCl solution is then added and the resulting phases are separated. The aqueous phase is extracted with ethyl acetate, the organic phases being washed with saturated NaHCO3 solution and with saturated NaCl solution, then dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether-ethyl acetate: 80-20) to yield the title product in the form of an oil in a yield of 85%.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCC(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCC(C)C)cc3)cc2N=C(N)C1
Reaction time: 1 h

Procedure:
Isobutyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate) was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded isobutyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 7.19-7.21 (m, 1H), 7.01-7.06 (m, 1H), 6.87 (s, 1H), 3.80-3.85 (m, 2H), 3.58-3.69 (m, 6H), 3.46-3.53 (m, 2H), 2.82 (s, 2H), 1.80-1.89 (m, 3H), 1.66-1.75 (m, 2H), 0.90-0.98 (m, 3H), 0.81-0.87 (m, 6H); m/z (APCI-pos) M+1=492.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 61.7 %

Procedure:
In the same manner as in Example 18-4 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (212 mg, 1.37 mmol), tetrahydrofuran (10 mL), oxalyl chloride (180 μL, 2.07 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (296 mg, 0.950 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (261 mg, 61%) was obtained as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=4F)[C:15]=3[CH3:35])=[CH:11][C:10]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:42][S:43]([OH:45])=[O:44].[Na]>CC(N(C)C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=4[S:43]([CH3:42])(=[O:45])=[O:44])[C:15]=3[CH3:35])=[CH:11][C:10]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CS(=O)O
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reaction time: 2 h

Procedure:
The N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinolin-4-amine (66 mg, 0.112 mmol) and methanesulfinic acid, sodium salt (12.0 mg, 0.112 mmol) was added to dimethylacetamide (0.24 mL) and placed in a microwave reactor for 2 h at 150° C. An LCMS was taken and ˜35% of starting material had converted to desired product. The mixture was reheated and stirred at 150° C. for 4 h. The reaction was then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (1×30 mL) and brine (1×30 mL) and dried over magnesium sulfate. The mixture was purified by reverse-phase preparative HPLC using a Phenomenex Gemini™ column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 20 minutes to provide N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)-5-nitrophenyl)-quinolin-4-amine after extraction with satd sodium bicarbonate. 1H NMR (CDCl3) δ ppm 8.48-8.56 (1H, m), 8.40-8.47 (1H, m), 8.31 (1H, s), 7.88-8.04 (1H, m), 7.67 (1H, dd, J=9.5, 2.6 Hz), 7.62 (1H, d, J=2.0 Hz), 7.38-7.47 (1H, m), 7.01 (1H, br. s.), 6.38 (1H, br. s.), 3.89-4.06 (4H, m), 3.76 (4H, t, J=4.6 Hz), 3.37-3.56 (2H, m), 2.93-3.28 (9H, m), 2.03 (3H, s). Mass Spectrum (ESI) m/e=623.3.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]([CH2:13][CH3:14])[CH3:12])[N:10]=[C:4]2[CH:3]=1.[C:15](=[O:22])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[NH2:16].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:18]([O:17][C:15](=[O:22])[NH:16][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]([CH2:13][CH3:14])[CH3:12])[N:10]=[C:4]2[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCN(C)c1nc2cc(Br)ccn2n1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CCN(C)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Temperature: 100 °C
Reaction time: 60 h
Yield: 81.3 %

Procedure:
To an argon purged solution of 7-bromo-N-ethyl-N-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (549 mg, 2.15 mmol) in dioxane (20.6 ml) were added tert-butyl carbamate (303 mg, 2.58 mmol), cesium carbonate (982 mg, 3.01 mmol), tris(dibenzylideneacetone) dipalladium(0) (39.4 mg, 43.0 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (49.8 mg, 86.1 mmol). The resulting mixture was heated to 100° C. and stirred for 2.5 days (weekend) under argon atmosphere. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using heptane/ethyl acetate 10-50% as eluent affording [2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (509 mg, 81.2%) as a white solid. mp: 181-183° C., MS: m/z=292.3 (M+H+)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21](=[O:34])[CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:21](=[O:34])[CH:20]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccn(CCOc3ccccc3)c(=O)c2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(C2CCNCC2OCc2ccc3ccccc3c2)ccn1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
20 mg (0.036 mmol) of tert-butyl (3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-1-(2-phenoxy-ethyl)-1',2',3',4',5',6'-hexahydro-1H-[4,4']bipyridin-2-one-1'-carboxylate were dissolved in 3 ml of methylene chloride, treated with 40 mg (0.18 mmol) of anhydrous zinc bromide and stirred at room temperature for 3 hours. Thereupon, the reaction mixture was poured into aqueous sodium carbonate solution this was extracted with methylene chloride. The combined methylene chloride phases were dried over magnesium sulphate and concentrated, and the thus obtained residue was chromatographed on silica gel with a 9:1 mixture of methylene chloride and methanol as the eluent. Therefrom there were obtained 5.8 mg (35% of theory) of (3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-1-(2-phenoxy-ethyl)-1',2',3',4',5',6'-hexahydro-1H-[4,4']bipyridin-2-one in the form of and amorphous, colourless solid; MS: 455 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15](=[O:17])[CH3:16])[C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[C:18]1(C)C=CC=CC=1.CO.[Si](C=[N+]=[N-])(C)(C)C.CCCCCC>CCCCCC>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15](=[O:17])[CH3:16])[C:6]=1[C:7]([O:9][CH3:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(OC(C)=O)c1C(=O)O
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1c(OC(C)=O)cccc1OC(C)=O

Procedure:
To a stirred 4° solution of Part B 2,6-diacetoxybenzoic acid (5.8 g, mmol) in 4:1 PhMe/MeOH (25 mL) was added 17 mL of 2M TMSCHN2/hexane over 10 min. After tlc analysis (1:1 ETOAc/hexane) revealed complete conversion, the volatiles were removed using a rotary evaporator and the residue purified by silica gel chromatography. 1:1 CH2Cl2/hexane-CH2Cl2 eluted 4.5 g of methyl 2,6-diacetoxybenzoate.
Reaction SMILES: NC1SC=C(/C(=N/OC(C(OC(C)(C)C)=O)(C)C)/C(N[C@H:11]2[C@@H:14]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[N:13]([S:20]([OH:23])(=[O:22])=[O:21])[C:12]2=[O:24])=O)N=1.[Na].FC(F)(F)C(O)=O>>[C:17]([O:16][CH2:15][CH:14]1[N:13]([S:20]([OH:23])(=[O:22])=[O:21])[C:12](=[O:24])[CH2:11]1)(=[O:19])[NH2:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCC1CC(=O)N1S(=O)(=O)O

Procedure:
2.28 g of (3S,4S)-3-[(2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid-sodium salt are stirred at 0° C. with 5 ml of trifluoroacetic acid. After additional stirring at room temperature for 30 minutes the excess trifluoroacetic acid is removed in vacuo and the remaining oil treated with 100 ml of ether. The resulting crystals are filtered off, washed with ether and dried in vacuo. The product is purified by reverse phase chromatography and lyophilized. (3S,4S)-3-](Z)-2-(2-Amino-4-thiazolyl)-2-[[1-carboxy-1-methylethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidine-sulfonic acid is obtained; [α]D =+35.7° (c=0.3 in water).
Reaction SMILES: C(O[Na])(C)(C)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][CH:10]=1.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH2:17][CH3:18]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(N(C)C2C=CC=CC=2)C=1P(C1CCCCC1)C1CCCCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:17]([CH3:18])[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:11][CH:10]=1
Reactant: COc1ccc(Cl)cc1
Reactant: CCC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 87.1 %

Procedure:
To a flame-dried and nitrogen filled Schlenk vessel were added Pd(OAc)2 (6.7 mg, 0.030 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyl(dicyclohexyl)phosphine (18.3 mg, 0.045 mmol), t-BuONa (115.4 mg, 1.2 mmol), and p-methoxyphenyl chloride (142.1 mg, 1.0 mmol)) in 1.5 mL of toluene sequentially. After being stirred for about 2 min at room temperature, propiophenone (160.9 mg, 1.2 mmol) in 1.5 mL of toluene were added. The resulting mixture was heated at 110° C. with a preheated oil bath. After 17.5 h, the reaction was complete as monitored by GC. The reaction mixture was then cooled and quenched with 10 mL of Et2O. After transferring the mixture into separatory funnel, the reactor was further washed with 10 mL of Et2O and 10 mL of HCl aqueous solution (5%). The combined mixture was extracted with Et2O (10 mL×2), washed with 20 mL of saturated NaHCO3 aqueous solution, and dried over anhydrous Na2SO4. Filtration, evaporation, and purification by chromatography (petroleum ether/ethyl acetate=80/1) on silica gel afforded 2-(4′-Methoxyphenyl)-1-phenyl-1-propanone (209.4 mg, 87%) as a liquid: 1H NMR (300 MHz, CDCl3) δ 8.00-7.92 (m, 2H, ArH), 7.52-7.43 (m, 1H, ArH), 7.42-7.35 (m, 2H, ArH), 7.24-7.18 (m, 2H, ArH), 6.86-6.80 (m, 2H, ArH), 4.65 (q, J=6.9 Hz, 1H, CH), 3.75 (s, 3H, OCH3), 1.52 (d, J=6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 200.5, 158.4, 136.5, 133.4, 132.6, 128.73, 128.69, 138.4, 114.3, 55.1, 46.9, 19.5; IR (neat) v (cm−1) 3061, 2972, 2931, 2836, 1682, 1609, 1596, 1511, 1448, 1302, 1248, 1221, 1178, 1034, 1002; MS (70 eV, EI) m/z (%): 240 (M+, 4.46), 135 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:16]N(C=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1I
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1I
Temperature: 23 °C
Yield: 96 %

Procedure:
A solution of 5-chloro-2-iodobenzoic acid (3.0 g, 10.62 mmol), SOCl2 (12 mL) and DMF (0.6 mL) was gently warmed with a heat gun until the mixture became homogeneous (15 min). The solution was maintained at 23° C. for additional 30 min and then the solution was concentrated. MeOH (24 mL) was added to the crude residue and the solution was maintained at 23° C. for 30 min. The solution was concentrated and the residue was purified by flash chromatography on Biotage silica gel cartridge (cyclohexane to cyclohexane:EtOAc=85:15) to afford methyl 5-chloro-2-iodobenzoate (3.02 g, 10.20 mmol, 96%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](Cl)=[O:5].[CH3:9][O:10][C:11]1[C:19]2[N:18]=[C:17]([CH2:20][CH2:21][CH2:22][N:23]([CH3:42])[CH2:24][CH2:25][C:26]3([OH:41])[CH2:32][CH:31]4[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:34][CH:27]3[CH2:28][CH2:29][CH2:30]4)[NH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[C:19]2[N:18]=[C:17]([CH2:20][CH2:21][CH2:22][N:23]([CH3:42])[CH2:24][CH2:25][C@:26]3([O:41][C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH2:32][C@@H:31]4[C:33]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:34][C@H:27]3[CH2:28][CH2:29][CH2:30]4)[NH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCCC3C=C4c3ccccc3)nc12
Reactant: O=C(Cl)CC(F)(F)F
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)CC(F)(F)F)C[C@H]4CCC[C@@H]3C=C4c3ccccc3)nc12

Procedure:
Prepared according to procedure P1.4 in Example 1A using 3,3,3-trifluoropropionyl chloride and rac-(1R*,5R*,6R*)-6-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-8-phenyl-bicyclo[3.2.2]non-8-en-6-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[F:15][C:16]1[CH:22]=[C:21]([O:23][C:24]2[C:29]3=[N:30][CH:31]=[C:32]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[N:33]=[C:28]3[N:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[C:21]([O:23][C:24]2[C:29]3=[N:30][CH:31]=[C:32]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[N:33]=[C:28]3[N:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:17]=1[NH:18][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:14]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CN1CCN(c2cnc3c(Oc4ccc(N)c(F)c4)ccnc3n2)CC1
Product: CN1CCN(c2cnc3c(Oc4ccc(NC(=O)Nc5cc(C(F)(F)F)ccc5F)c(F)c4)ccnc3n2)CC1

Procedure:
Method F3 was used with 2-Fluoro-5-(trifluoromethyl)phenyl isocyanate and 2-fluoro-4-(3-(4-methylpiperazin-1-yl)pyrido[3,2-b]pyrazin-8-yloxy)aniline to give the title compound as a yellow solid. Yield: 30 mg (64%).