Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH:10]=[CH:11][C:12](=[O:21])[CH2:13]4.[H][H].O.C(=O)(O)[O-].[K+]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)C=CC(=O)C3
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A solution of 7,8-didehydro-3,14-dimethoxy-17-methylmorphinan-6-one (3) (4.30 g, 13.72 mmol) in acetic acid (80 ml) was hydrogenated over 1.72 g of Pd/C (10%) at 3 atmospheres pressure until the hydrogen uptake was complete. The mixture was filtered through Celite and the solution concentrated under reduced pressure to give a clear oil. This oil was treated with water (100 ml) and potassium bicarbonate was added until the solution became basic. The mixture was extracted with methylene chloride (3×100 ml) whereupon the organic layer was separated, dried over MgSO4 and filtered. The filtrate was concentrated under vacuum to give 4.19 g (97% theory) of the desired product as a colorless solid (m.p. 152°-156° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:15][Mg]Br.C(OCCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:14])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nnn(-c2cccc(Cl)c2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (75.6 mg, 0.362 mmol) was dissolved in THF (2 mL) under argon and the flask was immersed in ice. Methyl magnesium bromide (1M solution/butyl ether 0.51 mL, 0.507 mmol) was added dropwise while the reaction was cooled in ice. After fifteen minutes at 0° C., the ice bath was removed and the reaction was allowed to stir at room temperature for two hours. 1M Hydrochloric acid was added to quench the reaction and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (3% MeOH/CH2Cl2) to yield the title compound as a clear oil (62.4 mg, 77%). 1H NMR (CDCl3) δ (ppm): 8.18 (s, 1H), 8.06 (m, 1H), 7.50 (m, 2H), 5.32 (m, 1H), 2.69 (d, 1H), 1.76 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.CCN(CC)CC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCCC(CO)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 2.07 g (16 mmol) 1-methyl-3-piperidinemethanol, 3.35 g (18 mmol) p-toluensulfonyl chloride, 0.58 g (5 mmol) 4-dimethylaminopyridine and 2.23 mL (16 mmol) NEt3 in 30 mL DCM was stirred for 2 h at room temperature. The mixture was washed with water and evaporated to dryness to yield 4.5 g (99%) of the title compound as yellow oil which was used without further purification. MS(m/e): 284.1 (MH+).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH3:16]>CCOC(C)=O>[CH2:15]([O:17][C:18](=[O:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:22]=1)[CH3:16]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Carboxylic acid (56)(50 mg, 0.27 mmol) was coupled to aniline (64)(52 mg, 0.27 mmol) using Method C. During this reaction, partial hydrolysis occurred. The residue was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[Cl:16][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:21][CH2:20]1
Reactant: FC(F)(F)c1ccc(N2CCC(COc3c(Cl)cc(OCc4ccccc4)cc3Cl)CC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1cc(Cl)c(OCC2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(Cl)c1

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step B, by the treatment of 2.5 grams (0.0049 mole) of 1,3-dichloro-5-(phenylmethoxy)-2-({1-[5-(trifluoromethyl)(2-pyridyl)](4-piperidyl)}methoxy)benzene with hydrogen gas in the presence of 0.3 gram (catalyst) of 10% palladium on carbon in 25 mL of ethyl acetate and 50 mL of ethanol using a Parr hydrogenation apparatus. The yield of the subject compound was 2.0 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29](O)=[O:30])[CH:22]=[N:21]2)=[CH:16][CH:15]=1.N=C=N>C(Cl)Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:29]([C:23]1[CH:22]=[N:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:24]=1[C:25]([F:28])([F:26])[F:27])=[O:30]
Reactant: O=C(O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: N=C=N
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Trifluoromethyl benzylamine (0.014 mL, 0.100 mmole) was added to a suspension of 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.030 g; 0.109 mmol) and PS-Carbodiimide (0.2 g) in methylene chloride (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time the reaction mixture was filtered and concentrated to give 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide. LCMS m/z=432.3 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=[C:11]([CH3:23])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[OH:32][CH2:23][C:11]1[N:10]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCc2ccccc2)c(C(=O)c2ccccc2)n1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1nc(CO)ccc1OCc1ccccc1
Temperature: 50 °C
Yield: 97.5 %

Procedure:
113 g of 2-benzoyl-3-benzyloxy-6-methylpyridine was dissolved in 600 ml of dichloromethane. 96 g of 3-chloroperbenzoic acid was added thereto, followed by stirring under heating at 50° C. in an oil bath. After cooling in a water bath, an aqueous sodium sulfite solution and further an aqueous saturated sodium bicarbonate solution were added to the reaction solution. The organic phase was separated, further washed with an aqueous saturated sodium bicarbonate solution and brine. Then, it was dried over anhydrous magnesium sulfate and the solvent was removed. The resulting residue was dissolved in 200 ml of acetic acid anhydride, followed by heating under stirring at 150° C. for 3 hours in an oil bath. Then, the solvent was removed and 400 ml of methanol and 200 ml of an aqueous 2N sodium hydroxide solution were further added thereto, followed by heating under stirring at 60° C. for 3 hours in an oil bath. Activated carbon was added to the reaction solution. After stirring for a while, it was filtered off. Water was added to the filtrate to precipitate crystals. The resulting crystals were collected by filtration and vacuum-dried, to give 116 g of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].O>CN1C(=O)CCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])([O-:3])=[O:2]
Reactant: CCCNCCC
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCN(CCC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To an ice cooled solution of 2,4-dinitrofluorobenzene (9.3 g, 50 mmol) and K2CO3 (6.9 g, 50 mmol) in 40 ml NMP was added dropwise dipropylamine (6.07 g, 60 mmol) in 10 ml NMP. After stirring for 1 hr, the reaction mixture was poured into a separatory funnel containing 100 ml water and extracted 3×100 mls with ether. The combined organics were washed with 3×100 ml water, 100 ml brine, dried with anhydrous MgSO4 and concentrated, giving 13.1 g crude product. This material was pure enough to carry on to the next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13](=[O:15])[NH:33][CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH2:23])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[CH:2]=[CH2:3].[C:32](Cl)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23][C:32](=[O:34])[CH3:33])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(N)nc23)cc1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)=O)nc23)cc1-c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a mixture of 7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl][1,3]thiazolo[5,4-d]pyrimidin-2-amine (200 mg, 0.41 mmol) and pyridine (20 mL), was added acetyl chloride (0.30 mL, 4.2 mmol) at rt. After being stirred for 1 hour, acetyl chloride (0.30 mL, 4.2 mmol) was added at rt. After being stirred for 2 hours, the mixture was concentrated in vacuo. To the residue, were added sat. NaHCO3 and EtOAc. After being stirred for 30 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with ether to yield the title compound (204 mg, 90%) as a pale yellow solid. LCMS: (AA) ES+527, 529. 1H NMR (400 MHz, d6-DMSO) δ: 12.76 (s, 1H), 8.97 (s, 1H), 8.68 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.44 (dd, J=8.3, 2.3 Hz, 1H), 7.26-7.23 (m, 2H), 7.04 (d, J=1.3 Hz, 1H), 5.70-5.62 (m, 1H), 5.09-5.06 (m, 1H), 4.85-4.80 (m, 1H), 4.38 (d, J=5.3 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].CN(C)C=O.[S-2].[Na+].[Na+].I[C:21]1[CH:26]=[CH:25]C=[CH:23][CH:22]=1>O>[Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Br)c1
Reactant: Ic1ccccc1
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccccc2)cc1Br
Temperature: 50 °C

Procedure:
A solution of 2-bromo-4-thiocyanoaniline (91.6 g., 0.4 mole) and dimethylformamide is added dropwise to a solution of sodium sulfide (0.48 mole) and water, under nitrogen, and the resulting solution is heated at 50° C. for one hour. Cuprous oxide (34.33 g., 0.24 mole) and iodobenzene (97.9 g., 0.48 mole) are added and the mixture is heated at a heating bath temperature of 150° C. for 4.5 hours. The reaction is quenched with water, methylene chloride is added and the resulting mixture is filtered through filter aid to remove suspended solids. The aqueous and organic layers are separated, and the aqueous layer is extracted three times with methylene chloride. The methylene chloride extracts are combined, washed with water and dried. Removal of the drying agent and methylene chloride gives the desired product in 95% of the theoretical yield. A purified sample melts at 61°-63° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[NH2:17].C(N(C(C)C)C(C)C)C.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>C(Cl)Cl>[F:27][C:28]([F:45])([F:46])[C:29]1[CH:30]=[C:31]([C:39]([CH3:43])([CH3:44])[C:40]([NH:17][C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:41])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1NC(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of 925 mg (4.05 mmol) 2′-methyl-4-nitro-biphenyl-2-ylamine and 1.03 ml (6.08 mmol) N-ethyldiisopropylamine in 9 ml CH2Cl2 was cooled in an ice bath and a solution of 1.42 g (4.46 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml CH2Cl2 was added dropwise. The reaction mixture was kept at room temperature for 2 hrs. After addition of CH2Cl2, the organic layer washed with 1 N NaOH solution and 1 N HCl solution, dried (MgSO4) and evaporated to give 1.84 g (89%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2′-methyl-4-nitro-biphenyl-2-yl)-isobutyramide as yellow crystals, MS (ISP): 511.3 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:30]=[CH:29][C:14]([CH2:15][O:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH:31]([C@@H:33]1[C@@H:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:36][N:35]([C@H:44]([CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)[C:45]([O:47]CC2C=CC(OC)=CC=2)=[O:46])[CH2:34]1)=O>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:33]3[C@@H:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][N:35]([C@H:44]([CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)[C:45]([OH:47])=[O:46])[CH2:34]3)[CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:29][CH:30]=1)([O-:10])=[O:9]
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: CCCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 86.3 %

Procedure:
The title compound was prepared from 4-(N-((4-nitrobenzyl)oxycarbonyl)-N-(prop-1-yl)amino)-piperidine trifluoroacetate (21 mg, 0.048 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (14 mg, 0.028 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 15 mg (89%) of the title compound. ESI-MS: 621.4 (M+H); HPLC A: 2.61 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:36])[CH2:32][C:33](O)=[O:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:33](=[O:34])[CH2:32][CH:31]([CH3:36])[CH3:30])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: CC(C)CC(=O)O
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
To a solution of (R)-4-amino-5-(piperidin-2-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 15a, 500 mg, 1.44 mmol) in DMF (12 mL) was added triethylamine (399 uL, 2.88 mmol), 3-methylbutanoic acid (159 uL, 1.44 mmol), EDCI-HCl (276 mg, 1.44 mmol), and HOBt (220 mg, 1.44 mmol). The reaction mixture was stirred at room temperature, under nitrogen for 18 hrs, then was filtered and purified by HPLC (10-90% acetonitrile in water). The pure fractions were combined, concentrated and crystallized from ethanol and water to give the title compound as a white solid (73 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 0.89 (d, J=6.8 Hz, 6H), 1.37 (m, 1H), 1.51-1.70 (m, 4H), 1.78 (d, J=12.8 Hz, 1H), 2.01 (m, 1H), 2.13-2.27 (m, 2H), 3.02 (br s, 1H), 3.89 (br s, 1H), 4.18 (br s, 1H), 4.48 (t, J=9.2 Hz, 1H), 5.02 (br s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.82 (br s, 2H), 10.63 (s, 1H). MS 395 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Product: COc1cccc(-c2ccc3ccc(OC)cc3c2)c1

Procedure:
The title compound was prepared by reacting 7-methoxy-2-naphthyl trifluoromethanesulfonate (2.20 g, 7.18 mmol) with 3-methoxyphenylboronic acid (1.20 g, 7.90 (mmol) according to method A above to yield a white solid: mp 58-59° C.;1H NMR (CDCl3): δ 3.89 (3H, s), 3.93 (3H, s), 6.91-6.94 (1H, m), 7.15 (1H, dd, J=2.42 Hz, J=8.83 Hz), 7.19H, d, J=2.27 Hz), 7.23-7.25 (1H, m), 7.28-7.31 (1H, m), 7.37-7.42 (1H, m), 7.59 (1H, dd, J=1.56 Hz, J=8.46 Hz), 7.75 (1H, d, J=8.84 Hz), 7.83 (1H, d, J=8.45 Hz), 7.94 (s1H, s); MS (ESI) m/z265 (M+H)−.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]3[C:15]([F:18])([F:17])[F:16])[C:5]=2[CH2:19]O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CS([Cl:34])(=O)=O>O>[Cl:34][CH2:19][C:5]1[C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([F:18])([F:17])[F:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c([C@H]2CCCC[C@@H]2C(F)(F)F)noc1C1CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)[C@@H]1CCCC[C@H]1c1noc(C2CC2)c1CCl
Reaction time: 6 h

Procedure:
A cold (0°C.) solution of (5-cyclopropyl-3-((1S,2S)-2-(trifluoromethyl)cyclohexyl) isoxazol-4-yl)methanol (1.8 g, 6.2 mmol) dichloromethane was treated with Hunig's base (953 μL, 6.8 mmol) followed by methane sulfonyl chloride (508 L, 6.5 mmol). Afte(6 hr of stirring, the reaction was treated with H2O and phases separated. The organic phase was collected, dried (MgSO4), filtered, concentrated, and chromatographed (SiO2, linear gradient, 0-80% EtOAc in Hex) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 4.48 (dd, J=36.5, 12.6 Hz, 2H), 3.48 (m, 1H), 2.44 (m, 1H), 2.15 (ddd, J=25.5, 12.8, 3.6 Hz, 1H), 2.04-1.87 (m, 4H), 1.82-1.68 (m, 2H), 1.55 (m, 1H), 1.35 (m, 1H), 1.14 (m, 2H), 1.09 (m, 2H), MS m/z 308.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>CN(C1C=CN=CC=1)C.ClCCCl>[C:16]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:5][S:6][C:2]=1[NH:1][C:28](=[O:29])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[N:17]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-amino-3-(4-nitrophenyl)isothiazole-4-carbonitrile (394 mg, 1.60 mmol), N,N-diisopropylethylamine (0.836 mL, 4.8 mmol), and catalytic DMAP in 20 mL 1,2-dichloroethane at rt was added phenyl chloroformate (0.301 mL, 2.40 mmol) drop wise over 1 minute. The reaction mixture was stirred at rt for 22 hours, then added directly to a dry packed silica gel column eluting with CHCl3, then gradient 10% to 50% EtOAc in CHCl3. The title compound was obtained as a beige solid (131 mg, 22%) and used as is for the next step.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][CH2:7][C:8](Cl)=[O:9]>C(Cl)Cl>[Cl:6][CH2:7][C:8]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](N)CO
Solvent: ClCCl
Product: C[C@H](CO)NC(=O)CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of (R)-2-amino-propan-1-ol (2.0 g, 26.6 mmol) in 150 mL of DCM at −40° C. under nitrogen atmosphere was added dropwise chloroacetyl chloride (2.3 mL, 29.2 mmol) in 60 mL of DCM. The mixture was gradually warmed to 0° C. and was stirred for 2 hours. After the removal of the solvents the residue was diluted with 50 mL of 1:1 ethyl acetate/hexane, stirred for 30 min and filtered. The filtrate was concentrated to afford 2-chloro-N—((R)-2-hydroxy-1-methyl-ethyl)-acetamide as a liquid.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Nc1ccccc1
Reactant: Cc1ncc([N+](=O)[O-])cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc([N+](=O)[O-])cc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-5-nitronicotinic acid (364 mg, 2 mmol), aniline (186 mg, 2 mmol) and DIEA (774 mg, 6 mmol) in DMF (6 mL) is added HATU (798 mg, 2.1 mmol). The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed by rotary evaporation and the crude product is purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to afford -methyl-5-nitro-N-phenylnicotinamide as a light green solid. MS m/z 258.1 (M+1).