Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[O:4][CH2:5][C@H:6]([NH:8]C(OC(C)(C)C)=O)[CH3:7].[ClH:18]>CCOC(C)=O.O1CCOCC1>[ClH:18].[CH3:1][N:2]([CH3:17])[C:3](=[O:16])[O:4][CH2:5][C@H:6]([NH2:8])[CH3:7]
Reactant: C[C@H](COC(=O)N(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](N)COC(=O)N(C)C
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-[(tert-Butoxycarbonyl)amino]propyl dimethylcarbamate (16.0 mg, 0.0650 mmol) in EtOAc (0.2 mL) was added 4M of hydrogen chloride in 1,4-dioxane (0.5 mL) and stirred for 1 h. The volatiles were removed under reduce pressure to give the desired compound. LCMS: (M+H)=147.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19](I)[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH2:25]([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[CH3:26].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH2:25]([O:27][C:28](=[O:29])[C:30]1[CH:35]=[CH:34][C:33]([C:19]2[CH:18]=[C:17]([C:11]([OH:16])([C:12]([F:15])([F:14])[F:13])[CH:10]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])[CH3:24])[CH:22]=[CH:21][N:20]=2)=[CH:32][CH:31]=1)[CH3:26]
Reactant: COc1ccc(C(C)C(O)(c2ccnc(I)c2)C(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2cc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)ccn2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-(2-iodo-pyridin-4-yl)-butan-2-ol (Example 139, 92 mg), 4-ethoxycarbonylphenylboronic acid (42 mg) and 1,1,bis(diphenylphosphino)ferrocenpalladium(II)dichloromethane in dioxane (0.7 mL) was treated with water (0.4 mL) and 2N—Na2CO3 (0.351 mL) and stirred at 80° C. under argon for 16 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 1:2) to give the title compound as light yellow amorphous material (78 mg). MS (m/e)=494.2 (MH+).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[C:3]2[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccc(Cl)cc12

Procedure:
Prepared from δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (360 MHz, CDCl3) (Contains 20% δ-oxobenzenepentanoic acid) δ8.02 (1H, s), 7.52-7.33 (6H, m), 7.23-7.18 (1H, m), 7.10-7.07 (1H, m), 3.16-3.11 (2H, m), and 2.65-2.60 (2H, m).
Reaction SMILES: C([Li])CCC.C(#N)C.C(=O)=O.CC1(C)CCCC(C)(C)N1.[CH3:22][O:23][C:24]1[N:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1.[CH:32]1([NH:37][C:38]2[C:43](I)=[CH:42][N:41]=[C:40]([NH2:45])[N:39]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1.[NH4+].[Cl-]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH:32]1([NH:37][C:38]2[C:43]([C:29]3[CH:28]=[C:27]([O:30][CH3:31])[N:26]=[N:25][C:24]=3[O:23][CH3:22])=[CH:42][N:41]=[C:40]([NH2:45])[N:39]=2)[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: Nc1ncc(I)c(NC2CCCC2)n1
Reactant: COc1ccc(OC)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1cc(-c2cnc(N)nc2NC2CCCC2)c(OC)nn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
A solution of butyllithium (2.5 m solution in hexanes) (7.5 mL, 19 mmol) was added to cold (acetonitrile-dry ice bath, −34° C. internal), stirred 2,2,6,6-tetramethylpiperidine (3.4 mL, 20 mmol). The resulting mixture was allowed to stand at 0° C. (ice-H2O bath) for 30 min. The ice-H2O was then replaced with dry ice-2-propanol bath and the mixture was cooled to −0° C. THF (24 mL) was added. A pre-cooled (ice-H2O bath) solution of 3,6-dimethoxypyridazine (2.40 g, 17 mmol) in THF (40 mL) was added through a cannula over a period of 30 min. The internal temperature was observed fluctuating between −72° C. and −55° C. The resulting mixture was stirred at −70° C. for 1.5 h. A solution of zinc(II) chloride (0.5 M in THF) (34 mL, 17 mmol) was added through a syringe over a period of 15 min. The internal temperature fluctuated between −73° C. and −64° C. The cold bath was removed and the resulting mixture was allowed to warm up to rt (20.5° C.). A solution of compound 243 (1.7 g, 5.7 mmol) and tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol) in THF (20 mL) was added and the resulting mixture was heated at reflux for 18 h. Upon workup, the crude mixture was cooled in an ice-H2O before poured into ice and saturated NH4Cl aqueous solution and extracted with ethyl acetate (2×). The combined organics were combined, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM with Et3N) to give pure compound 316 (1.2 g, 66% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (1 H, s), 7.01 (1 H, s), 6.18-6.38 (3 H, m), 4.35-4.51 (1 H, m, J=7.3, 7.3, 7.3, 7.3, 7.0 Hz), 3.95 (3 H, s), 3.91 (3 H, s), 1.77-1.90 (2 H, m), 1.55-1.69 (2 H, m), 1.35-1.55 (4 H, m). LCMS-ESI (POS), M/Z, M+1: Found 317.2.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[Li]CCCC.[Br:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([F:25])[CH:24]=1)/[CH:14]=[N:15]/[S@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([C@H:14]([NH:15][S@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])[CH2:4][N+:1]([O-:3])=[O:2])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(F)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@H](C[N+](=O)[O-])c1cc(F)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 38.7 %

Procedure:
Nitromethane (1.0 mL, 17.20 mmol) was dissolved in THF (34.4 mL), then BuLi (2.5 M in hexanes) (7.22 mL, 18.06 mmol) was added at −78° C. The reaction mixture was stirred at −78° C. for 10 min, then warmed up to room temperature for 20 min. After cooling down to −78° C., (S,E)-N-(3-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (4.74 g, 15.48 mmol) in THF (6 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 20 min, warmed up to room temperature, and stirred at room temperature for 5 h. The reaction mixture was quenched by sat NH4Cl, and extracted by EtOAc. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-40%-100% EtOAC/heptane). Pure fractions were combined to yield (S)—N—((S)-1-(3-bromo-5-fluorophenyl)-2-nitroethyl)-2-methylpropane-2-sulfinamide (2.2 g, 5.99 mmol, 38.7% yield). LCMS (m/z): 367.1/369.1 (MH+), 0.89 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (s, 1H), 7.03 (d, J=9.0 Hz, 1H), 5.03 (q, J=5.7 Hz, 1H), 4.87-4.78 (m, 2H), 4.48 (d, J=5.1 Hz, 1H), 1.33-1.25 (m, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1.Cl>CN(C=O)C.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
DIPEA (114 mg, 0.15 mL, 0.88 mmol) was added drop wise to 2-bromo-5-fluoro-benzoic acid (77 mg, 0.35 mmol) in DMF (5 mL). EDCI (114 mg, 0.88 mmol) and HOBT (47 mg, 0.35 mmol) were added consecutively and, after 10 minutes, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenylamino-benzamide in its HCl salt form (100 mg, 0.29 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 80 mg (50% yield) of N-{2-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 94.48%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 3H), 7.4 (m, 4H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (dd, 2H), 3.6 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1.C([O-])(=O)C.[Na+]>>[CH3:13][N:14]([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][N:16]=1
Reactant: CN(C)c1ccc(N)cn1
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1nc(Nc2ccc(N(C)C)nc2)c2ccccc2n1

Procedure:
To a solution of 2-dimethylamino-5-nitropyridine (334 mg, 2 mmol) in 100 ml of methanol was added 5% Pd/C (100 mg, 0.94 mmol). The reaction mixture was hydrogenated under 45 psi at room temperature for 2 h, then it was filtered through a layer of celite (2.5 in d×2 in h) and washed with additional methanol (25 ml). The organic filtrate was concentrated to yield 200 mg (73%) of 2-dimethylamino-5-amino-pyridine as dark brown sticky solids. The title compound was prepared from 4-chloro-2-methyl-quinazoline (182.2 mg, 1.02 mmol), 2-dimethylamino-5-amino-pyridine (140 mg, 1.02 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 60 mg (21%) of paint yellow solids. 1H NMR (CDCl3): 8.43 (d, J=2.4 Hz, 1H), 7.95 (dd, J=2.7 Hz, J=9.3 Hz, 1H), 7.84-7.72 (m, 3H), 7.47 (t, J=8.1 Hz, 1H), 7.16 (brs, 1H), 6.61 (d, J=9.0 Hz, 1H), 3.12 (s, 6H), 2.65 (s, 3H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[N:11]([C:19](=[O:32])[CH2:20][N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[C:10]3[CH:33]=[CH:34][CH:35]=[CH:36][C:9]2=3)=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O>C(Cl)(Cl)Cl.C(#N)C>[C:22]1(=[O:31])[N:21]([CH2:20][C:19]([N:11]2[C@@H:12]3[CH2:18][CH2:17][CH2:16][C@@H:13]3[C:14](=[O:15])[NH:8][C:9]3[CH:36]=[CH:35][CH:34]=[CH:33][C:10]2=3)=[O:32])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: COc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)[C@@H]2CCC[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of (3aR*,10aS*)-9-(4-methoxybenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (9.89 g, 19 mmol) in chloroform (150 mL) was added a solution of ammonium cerium (IV) nitrate (31.3 g, 57 mmol) and water (5 mL) in acetonitrile (150 mL), and the mixture was stirred for 10 minutes at room temperature. The reaction mixture was poured into water (300 mL), which was subjected to extraction twice with chloroform. Organic layers were combined, washed with water and a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica-gel column chromatography (chloroform-ethyl acetate 2:1) to a crystalline product, which was washed with chloroform-diisopropyl ether to give 3.7 g (yield 50%) of the titled compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[O:22][C:21](=[O:23])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.I[CH2:25][CH:26]=[CH:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH4+].[Cl-]>C1COCC1>[CH2:30]([O:29][CH2:28][CH:27]=[CH:26][CH2:25][C@H:20]1[CH2:19][C@H:18]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=2)[O:22][C:21]1=[O:23])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1CC[C@H](c2ccc(F)cc2)O1
Reactant: ICC=CCOCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@@H](c2ccc(F)cc2)C[C@@H]1CC=CCOCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (4.6 mL, 4.6 mmol, 1M in THF) in anhydrous 40 mL THF at −70° C. was slowly added over 15 minutes ((R)-5-(4-fluorophenyl)dihydrofuran-2(3H)-one (685 mg, 3.8 mmol) as a solution in 4 mL THF. After the reaction mixture was stirred for 30 min at −70° C. a pre-cooled solution of (4-Iodo-but-2-enyloxymethyl)-benzene (1.3 g, 4.6 mmol) in 4 mL of THF was slowly added. The resulting mixture was stirred at −70° C. for 1 h and the temperature was slowly raised to room temperature over a period of 2 h. The mixture was poured into 20 mL saturated NH4Cl and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 827 mg of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[CH2:1]([O:5][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.4 %

Procedure:
To a solution of 3-buten-1-ol (540 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 650 mg of the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=O)C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.C(O)(=O)C>[CH:33]1([N:32]2[C@@H:28]3[C@@H:27]([CH2:31][CH2:30][CH2:29]3)[C:25]([OH:24])=[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=4[S:13](=[O:15])(=[O:14])[N:12]=3)[C:17]2=[O:18])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)C1CCCC1NC1CCCCC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(C3CCCCC3)C1=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4] thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (0.072 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (72.8 mg, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69.0 mg, 0.36 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(1-cyclohexyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (48 mg, 0.094 mmol, 31.5%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.19 (2H, m), 1.31-1.40 (2H, m), 1.48-2.04 (12H, m), 3.06 (3H, s), 3.26-3.35 (1H, m), 3.91-4.05 (1H, m), 4.23-4.35 (1H, m), 7.50-7.57 (3H, m), 10.18 (1H, bs). LC-MS (ESI) calcd for C22H28N4O6S2 508.15, found 509.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:6][CH:7]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3cccc(Cl)c3Cl)cc2)c2ccc3c(c2N1)CCCC3
Yield: 91.8 %

Procedure:
By using 5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (32 mg, 0.100 mmol) obtained in Example 55, and (2,3-dichlorophenyl)methanesulfonyl chloride (31 mg, 0.119 mmol), the title compound (50 mg, yield 92%) was obtained in the same manner as that of Example 145.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23](O)=[C:18]3[CH:17]=[N:16]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]>>[Cl:6][C:7]1[C:8]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([Cl:3])=[C:18]3[CH:17]=[N:16]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(O)ncnc21
Product: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21

Procedure:
Phosphorus oxychloride (7.93 mL, 85.03 mmol) was added to 3-chloro-2-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH5) (1.155 g, 4.25 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14]O[C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.C1(C)C=CC=C(C2[S:34]C=NC=2C(O)=O)C=1>>[NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][S:34][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cc1cccc(-c2scnc2C(=O)O)c1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Product: Cc1cccc(-c2scnc2C(=O)Nc2cnn(CCN)c2)c1

Procedure:
The title compound was synthesized according to above mentioned procedure for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide, starting from 5-(m-tolyl)thiazole-4-carboxylic acid. LC-MS conditions B: tR=0.54 min, [M+H]+=328.10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2].[N:40]1[CH:45]=[CH:44][CH:43]=[C:42](B(O)O)[CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:42]4[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1

Procedure:
Suzuki Coupling Using Aryl Boronic Acids: A mixture of 3-[4-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (450 mg, 0.75 mmol), 3-pyridineboronic acid (120 mg, 0.97 mmol), triphenylphosphine (6 mg, 0.024 mmol), 2M aqueous sodium carbonate (3 mL) in n-propanol (15 mL) was sparged with nitrogen for 5 min. Palladium acetate (2 mg, 0.008 mmol) was added, and the reaction was heated to reflux under a blanket of nitrogen for 4 h. The reaction mixture was concentrated and then partitioned between water/EtOAc. The organic layer was dried (MgSO4) and concentrated to crude product (290 mg). This material was purified by silica gel column chromatography to yield 3-(2-(isopropoxycarbonylamino-methyl)-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid tert-butyl ester was obtained as a white solid (230 mg, 51%). 1H NMR (CDCl3) δ1.25 (d, 6H), 1.42 (s, 9H), 2.42 (s, 3H), 2.51 (t, 2H), 2.89 (t, 2H), 3.05 (t, 2H), 4.26 (t, 2H), 4.36 (d, 2H), 4.96 (m, 2H), 6.78 (dd, 1H), 6.87 (d, 1H), 7.21 (d, 1H), 7.47 (dd, 1H), 7.67 (d, 2H), 8.00 (dt, 1H), 8.12 (d, 2H), 8.65 (dd, 1H), 8.94 (s, 1H). MS [EI+] m/z 600 (M+H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>C(#N)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a stirring solution of 4-piperidone monohydrate hydrochloride (258.7 g, 1.68 mol) and diisopropylethylamine (590 ml, 3.39 mol) in acetonitrile (2.5 liter) is added 3,4-difluoronitrobenzene (186.3 ml, 1.68 mol). The mixture is heated to 80° C. and stirred overnight. The solvent is cooled to ambient temperature and removed under reduced pressure. The residue is partitioned between ethyl acetate and 10% aqueous HCl (1.20 liter each). The layers are shaken, and the organic layer is separated and washed with 10% HCl and saline (800 ml each). The organic layer is dried over MgSO4 and filtered. As the solvent is removed under reduced pressure a solid begins to precipitate out (˜¼ volume). The resulting slurry is cooled to 0-5° C. and filtered to afford 333.7 g of the title compound, 1H NMR (400 MHz, CDCl3) δ 2.65 (m, 4 H), 3.65 (m, 4 H), 6.98 (m, 1 H), 7.26 (s, 1 H), 8.00 (m, 1 H).