Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: CS(=O)(=O)NCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)NCCOc1cc(N)cc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
N-(2-((3-Nitro-5-(trifluoromethyl)phenyl)oxy)ethyl)-methanesulfonamide (1.7 g, 5.2 mmols, 1 eq) was dissolved in 50 L of MeOH. 10% Pd/C (170 mg, 10 weight %) was added and the reaction sparged with H2. The suspension was stirred for 5 h, then filtered trough Celite. The filtrate was stripped to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=3)[S:13][C:6]=12.Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=3)[S:13][C:6]=12
Reactant: COc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c[nH]1
Temperature: 85 °C
Yield: 98 %

Procedure:
To a flask containing a suspension of 419 (0.299 g, 0.753 mmol) in acetonitrile (8 mL) was added chlorotrimethylsilane (0.095 mL, 0.748 mmol) followed by sodium iodide (0.112 g, 0.748 mmol). The mixture was then heated to between 70 to 100° C. over 24 hours. Over this time four additional portions of chlorotrimethylsilane (0.095 mL each portion) and sodium iodide (0.112 g each portion) were added. The reaction mixture was then cooled to room temperature and the formed precipitate was collected by filtration, washed with NH4OH and water, and dried to provide title compound 420 as a brown solid (0.283 g, 98%). MS (m/z): 284.0 (M+H), 406.0 (M+Na).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([N:35]2[CH2:39][CH2:38][O:37][C:36]2=[O:40])[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([N:35]5[CH2:39][CH2:38][O:37][C:36]5=[O:40])[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C1OCCN1c1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(N5CCOC5=O)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(6-bromo-pyridin-2-yl)-oxazolidin-2-one.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[CH3:23]S(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC1C=CC=CC=1)[C@H]1CC[C@H](O)CC1)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][C:12]1([OH:15])[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]1
Reactant: CS(C)=O
Reactant: O=C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(O)CCC(N)CC1
Temperature: -78 °C
Yield: 82 %

Procedure:
4-(Dibenzylamino)cyclohexanone. A solution of dimethyl sulfoxide (5.77 mL, 81 mmol) in methylene chloride (20 mL) was added dropwise, to a solution of oxalyl chloride (3.26 mL, 37.2 mmol) in methylene chloride (150 mL) stirring at −78° C. After stirring for 15 min at −78° C., a solution of trans-4-(dibenzylamino)cyclohexanol (10.0 g, 33.9 mmol) in methylene chloride (100 mL) was added dropwise. After stirring at −78° C. for another 15 min, triethylamine (23.59 mL, 169 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture appeared as a suspension and was washed with brine (100 mL). The organic layer was separated, dried over magnesium sulfate and concentrated to give a colorless oil that was purified using silica gel flash column chromatography (5-100% ethyl acetate in hexanes) to give the title compound as a colorless oil (8.11 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.35-7.39 (m, 4H), 7.28-7.33 (m, 4H), 7.18-7.24 (m, 2H), 3.61 (s, 4H), 2.89-2.99 (m, 1H), 2.26-2.38 (m, 2H), 2.14-2.24 (m, 2H), 2.06 (td, J=2.81, 6.43 Hz, 2H), 1.81 (qd, J=4.27, 12.49 Hz, 2H). Rf=0.36 (TLC, 20% ethyl acetate in hexane); MS (ESI) m/z 294.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:20][CH:21]([F:33])[O:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.[NH4+].[Cl-]>CCOC(C)=O.C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH:21]([F:20])[F:33])[CH:24]=2)(=[O:31])=[O:30])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: Nc1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1cccc(OC(F)F)c1
Temperature: -78 °C
Yield: 93.6 %

Procedure:
To a THF (20 mL) solution of 3-amino-5-bromo-2-chloropyridine (1.197 g, 5.77 mmol, Asymchem, Morrisville, N.C.)) at −78° C. was added a THF solution of lithium bis(trimethylsilyl)amide (1.0 M, 11.5 mL, 11.5 mmol, Aldrich, St. Louis, Mo.). The solution was maintained for 5 min at −78° C. and then 3-(difluoromethoxy)benzenesulfonyl chloride (1.40 g, 5.77 mmol, Aldrich, St. Louis, Mo.) was added as a solid in a single portion. The solution was allowed to warm to rt, and maintained 1 h. The solution was poured into saturated aqueous NH4Cl (100 mL) and the resulting mixture was extracted with EtOAc (100 mL). The organic layer was dried (Na2SO4) and concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The residue was taken up in minimal CH2Cl2 and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (120 g) using a gradient of 98:2 Hexanes:EtOAc to 100% EtOAc to afford N-(5-bromo-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (2.235 g, 93.6% yield) as a colorless oil. LCMS (ESI positive ion) m/z: 414.9 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.54 (t, J=72.38 Hz, 1H); 7.33-7.42 (m, 2H); 7.51 (t, J=8.07 Hz, 1H); 7.58 (t, J=1.91 Hz, 1H); 7.61-7.68 (m, 1H); 8.13 (d, J=2.25 Hz, 1H); 8.19 (d, J=2.25 Hz, 1H).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:13]S(C3C=CC=CC=3)(=O)=O)[CH2:12][O:11][CH2:10]2)=[CH:5][C:4]=1[OH:23].CCOCC>CO>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:13])[CH2:10][O:11][CH2:12]2)=[CH:5][C:4]=1[OH:23]
Reactant: Cc1ccc(C2(CS(=O)(=O)c3ccccc3)COC2)cc1O
Agent: [Mg]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(C2(C)COC2)cc1O
Reaction time: 0.03 h

Procedure:
Magnesium (granulate) (8.70 g, 358 mmol) was added to a solution of crude 2-methyl-5-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenol (7.6 g, 23.9 mmol) in MeOH (100 mL). The resulting mixture was stirred for 2 min in an ultrasound bath. The flask was then fitted with a condenser. Stirring was continued for 3 h, at which point the reaction mixture turned cloudy and off white in color. The reaction was exothermic, which caused the solvent to reflux. Water bath was added to lower the reaction mixture temperature to room temperature. The reaction mixture was then stirred overnight and became heterogeneous and pale orange in color. Et2O (525 mL) was added, followed by Na2SO4.10H2O (85 g). The resulting mixture was stirred for 2 h at room temperature and Celite® was then added. The resulting mixture was stirred for another 1 h and filtered through a Buchner funnel packed with Celite®. The cake was washed with EtOAc (2×) and MeOH (1×). The light yellow filtrate was concentrated and the residue was triturated with CHCl3 (220 mL) and filtered. The filtrate was concentrated to provide 2-methyl-5-(3-methyloxetan-3-yl)phenol. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.14 (d, J=7.83 Hz, 1 H) 6.73 (d, J=7.58 Hz, 1 H) 6.69 (d, J=1.77 Hz, 1 H) 4.92 (d, J=5.31 Hz, 2 H) 4.61 (d, J=5.56 Hz, 2 H) 2.26 (s, 3 H) 1.72 (s, 3 H)
Reaction SMILES: C1(NC(OCC)=O)C=CC=CC=1.ClCCCl.F[N+:18]1[C:23]([S:24]([O-:27])(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:28]>O>[Cl:28][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([S:24]([OH:27])(=[O:26])=[O:25])[N:18]=1
Reactant: O=S(=O)([O-])c1cccc(Cl)[n+]1F
Agent: CCOC(=O)Nc1ccccc1
Solvent: O
Solvent: ClCCCl
Product: O=S(=O)(O)c1cccc(Cl)n1

Procedure:
A 25 ml egg-plant type flask was flushed with argon, and 85.9 mg (0.52 mmol) of phenylurethane, 2 ml of dry 1,2-dichloroethane and 110.2 mg (0.52 mmol) of N-fluoro-2-chloropyridinium-6-sulfonate were charged. The flask was immersed in an oil bath of 80° C. and heated for 72 hours. Then, 20 ml of water was added thereto, and the mixture was extracted with methylene chloride (20 ml×3 times). 2-Chloropyridine-6-sulfonic acid formed after the reaction was all transferred to the aqueous layer. The organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure. The residue was purified by thin layer chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 58.6 mg (conversion yield: 73%) of 2-fluorophenylurethane, 4.9 mg (conversion yield: 6%) of 4-fluorophenylurethane and 2.8 mg (conversion yield: 3%) of 2,4-difluorophenyl-urethane. 14.1 mg of phenylurethane was recovered (recovery rate: 16%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][NH2:23]>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:23][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH3:13])=[O:12])[CH2:2]2
Reactant: COc1ccccc1CCN
Reactant: O=C(O)CC1CN2CCC1CC2
Product: COc1ccccc1CCNC(=O)CC1CN2CCC1CC2
Yield: 15 %

Procedure:
Using general procedure I, (1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (200 mg, 1.20 mmol) and 2-(2-methoxy-phenyl)-ethylamine gave the title compound as a white solid (60 mg, 15%). 1H NMR (400 MHz, CD3OD) δ 7.17 (t, J=7.2 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.84 (t, J=7.6 Hz, 1H), 3.89 (s, 3H), 3.35-3.45 (m, 3H), 3.21-3.31 (m, 3H), 2.76-2.83 (m, 3H), 2.29-2.45 (m, 3H), 1.82-2.01 (m, 3H), 1.72-1.81 (m, 2H) ppm. 13C NMR (400 MHz, CD3OD) δ 172.0, 158.0, 130.4, 127.8, 127.2, 120.2, 110.4, 54.6, 52.0, 46.4, 45.9, 39.1, 38.3, 30.7, 30.2, 23.8, 17.9 ppm. Purity: 92.4% HPLCMS (210 nm); retention time 1.59 min; (M+1) 303.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:21][CH2:20][N:19]3[C@H:14]([CH2:15][O:16][CH2:17][CH2:18]3)[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[Sn](Cl)Cl.Cl>O1CCOCC1.C1COCC1>[CH2:15]1[C@@H:14]2[CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][O:16]1
Reactant: COc1cc(N2CCN3CCOC[C@@H]3C2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cc(N2CCN3CCOC[C@@H]3C2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To (9aS)-8-[3-(methyloxy)-4-nitrophenyl]octahydropyrazino[2,1-c][1,4]oxazine (0.196 g, 0.660 mmol) in dioxane (8 mL) and THF (4 mL) cooled to 0° C. was added tin(II) chloride (0.544 g, 2.86 mmol) in HCl (2.20 mL, 37% in water, 24.6 mmol) dropwise. The reaction warmed to rt and stirred overnight. An additional amount of tin(II) chloride (1.00 g, 5.27 mmol) in HCl (4.40 mL, 37% in H2O, 49.1 mmol) was added to the reaction. When complete by TLC, the reaction was cooled to 0° C. and quenched with 6N NaOH (50 mL). The mixture was poured into H2O/EtOAc and separated. The organic layer was washed with brine and the resultant aqueous layer was back extracted with EtOAc. The combined organic layer was dried (MgSO4) and concentrated to provide the title compound of step B (0.170 g, 0.640 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) b ppm 1.47 (dt, J=14.9, 6.5 Hz, 1H), 1.65-1.74 (m, 1H), 2.14-2.25 (m, 1H), 2.26-2.31 (m, 1H), 2.55-2.66 (m, 1H), 2.74 (d, J=10.8 Hz, 1H), 3.10 (t, J=10.4 Hz, 1H), 3.17 (d, J=11.5 Hz, 1H), 3.31 (d, J=11.7 Hz, 1H), 3.37 (q, J=6.2 Hz, 1H), 3.47 (td, J=11.3, 2.1 Hz, 1H), 3.60 (t, J=6.7 Hz, 1H), 3.63-3.74 (m, 4H), 4.41 (t, J=5.3 Hz, 1H), 4.46 (s, 1H), 6.23 (dd, J=8.3, 2.5 Hz, 1H), 6.42-6.50 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CCOc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 29 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-ethoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (50 mg, 29%) which was obtained as a white solid. MS (ESI): m/e=346.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:26]=[O:27])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:32]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:26]=[O:27])=[CH:10][N:9]=1)=[O:32])[CH3:2]
Reactant: CCOCCOc1cc2c(C=O)cnc(Cc3cccc(OCC)c3)c2cc1OC
Reactant: O=[Se]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOCCOc1cc2c(C=O)cnc(C(=O)c3cccc(OCC)c3)c2cc1OC
Temperature: 120 °C

Procedure:
To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (61 mg, 0.15 mmol) was added selenium dioxide (132 mg, 1.20 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (60 mg, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:28]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]5)=[CH:38][CH:39]=4)[N:18]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:42]([OH:44])([C:41]([F:46])([F:45])[F:40])=[O:43]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccc(F)c(F)c5)CCCCC4)n3)cc2)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccc(F)c(F)c5)CCCCC4)n3)cc2)C1
Reaction time: 0.5 h

Procedure:
To tert-butyl 1-(4-(5-(2-(1-(3,4-difluorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (50.1 mg, 0.093 mmol) was added trifluoroacetic acid (2 mL, 26.0 mmol), and the mixture was stirred for 30 mins. The acid was evaporated off to give an oily residue. It was purified by preparative HPLC (Column: Phen-Luna 5u C18 21.2×100 mm, Sol A: 10% MeOH—90% H2O—0.1% TFA, Sol B: 90% MeOH—10% H2O—0.1% TFA, Start % B: 50, Final % B: 100, Gradient Time: 10 mins) to give pure 1-(4-(5-(2-(1-(3,4-difluorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid, TFA (40.5 mg, 0.067 mmol, 71.5% yield) as a foamy solid. LC/MS: m/e 482.14 (M+H)+. 1H NMR (400 MHz, CCl3D) δ ppm 12.51 (1H, br. s.), 8.02 (2H, d, J=7.03 Hz), 7.47 (2H, d, J=7.91 Hz), 6.98-7.21 (3H, m), 4.28-4.62 (4H, m), 4.01-4.24 (2H, m), 3.53-3.83 (1H, m), 2.49-2.68 (2H, m), 1.94-2.18 (4H, m), 1.21-1.72 (8H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1.[CH2:11]([NH:14][CH2:15][CH:16]=[CH2:17])[CH:12]=[CH2:13]>>[NH2:1][C:2]1[N:3]=[C:4]([CH2:9][Cl:10])[CH:5]=[C:6]([N:14]([CH2:15][CH:16]=[CH2:17])[CH2:11][CH:12]=[CH2:13])[N:7]=1
Reactant: C=CCNCC=C
Reactant: Nc1nc(Cl)cc(CCl)n1
Product: C=CCN(CC=C)c1cc(CCl)nc(N)n1

Procedure:
3.56 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine and 3.9 parts of diallylamine were reacted together according to the method of Example 15 to give 2-amino-4-chloromethyl-6-diallylaminopyrimidine m.p. 53°-55° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5](C(O)=O)[NH:6]2.N1C2C(=CC=CC=2)C=CC=1>[Cr]([O-])([O-])=O.[Cu+2]>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1Br
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Product: COc1ccc2[nH]ccc2c1Br
Temperature: 245 °C
Yield: 67 %

Procedure:
4-Bromo-5-methoxyindole-2-carboxylic acid (1.25 g, 4.19 mmol), quinoline (15 ml) and copper chromite (313 mg) were mixed together. Nitrogen was gently bubbled through the mixture for 5 minutes, then the mixture heated quickly to 245° C. under an atmosphere of nitrogen. After 90 minutes the mixture was cooled to ambient temperature diluted with ethyl acetate (100 ml) and washed with 2M aqueous hydrochloric acid (60 ml). The ethyl acetate layer was filtered, the filtrate dried (MgSO4) and the solvent evaporated. The residue was purified by silica column chromatography eluting with dichloromethane/hexane (1/1) to give 4-bromo-5-methoxyindole (635 mg, 60%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[C:3]=1[CH:9]=O.[Cl:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][NH2:20]>CN1C(=O)CCC1>[Cl:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]2[CH:9]=[N:20]1
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1ccc(F)cc1Cl
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)c(Cl)c1
Temperature: 185 °C
Reaction time: 36 h
Yield: 13.6 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added 4-iodo-2-fluoro-3-formylpyridine (314 mg, 1.25 mmol), (2-chloro-4-fluorophenyl)hydrazine (210 mg, 1.31 mmol), and anhydrous NMP (5 mL). The reaction mixture was purged with argon, heated at 185° C. for 2 h, and then at 140° C. for 36 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A and the crude product was purified by Biotage Silica gel chromatography using a 80 g Thompson Single Step™ silica cartridge with a linear gradient from 100% hexanes to 100% CH2Cl2 over 12 column volumes to give 63.5 mg (13.6%) of the title compound as a pale yellow solid, LC/MS (Condition B): ret. T=3.7 min, (M+H)+ 373.88, 375.88 and 149.3 mg (30.3%) of the hydrazone intermediate as a pale yellow solid, LC/MS (Condition B): ret. T=4.2 min, (M+H)+ 393.90, 395.90.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH2:19][C:20]1[CH:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:19][C:20]3[CH:21]=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=[CH:24][C:25]=3[O:26][CH3:27])=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: COc1ccc(-c2ccccc2)cc1N
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cc(-c3ccccc3)ccc2OC)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-amino-4-methoxy-biphenyl as in Example 1 d. 1H-NMR (400 MHz, d8-DMSO) δ 8.85 (s, 1H), 8.55 (br, 1H), 7.70 (d, 1H), 7.60 (d, 2H), 7.46 (t, 2H), 7.38 (dd, 1H), 7.33 (t, 1H), 7.16 (d, 1H), 7.02 (dd, 1H), 6.98 (d, 1H), 6.72 (br, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 426.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].O1CCCC1>[OH-].[Na+]>[C:15]1([O:14][C:12]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(=O)O)c1)Oc1ccccc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
After 274.3 g of 3-aminobenzoic acid was dissolved in 4L of a 0.5N aqueous solution of sodium hydroxide, a solution of 328.8 g of phenyl chloroformate in 1L of tetrahydrofuran was added dropwise at 10° C. The reaction mixture was stirred at the same temperature for 1 hour, and then at room temperature for 1 hour. Crystals so precipitated were collected by filtration with suction, washed with water, dried and then recrystallized from ethanol to obtain 412 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]([NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=1)([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].Cl.[CH3:31][NH2:32]>>[CH2:1]([C:3]([NH:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=1)=[O:29])([C:4](=[O:6])[NH:32][CH3:31])[CH2:7][CH3:8])[CH3:2]
Reactant: CN
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)O
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid and methanamine hydrochloride as starting materials. MS (EI): m/e=432.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:20]([CH3:22])[CH3:21])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:20]([CH3:22])[CH3:21])[N:13]=1)(=[O:9])[NH2:10]
Reactant: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc1C(C)C
Temperature: 140 °C
Yield: 32.4 %

Procedure:
To a solution of 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (199 mg, 618 μmol) in NMP (2.06 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (532 mg, 2.47 mmol) in four portions approximately every 12 h while heating at 140° C. After a total heating time of 48 h, the mixture was cooled, diluted with ethyl acetate and brine, then the phases were separated and the organic phase washed twice more with brine. The organic phase was concentrated in vacuo then purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (100 mg, 200 μmol, 32%) as a brown solid. MS (EI/CI) m/z: 500.4 [M+H].