Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (3.71 g, 7.32 mmol) and 2-amino-2-methyl-1-propanol (2.10 ml, 22.0 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1

Procedure:
4,4,4-Trifluoro-3-oxo-butyronitrile and phenylhydrazine were combined by the procedure of Example B22 to provide 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine. 1H-NMR (400 MHz, DMSO-d6) δ 7.59-7.50 (m, 4 H), 7.42 (m, 1 H), 5.78 (s, 1 H), 5.73 (br s, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](I)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[N:13]1C=CC=C[CH:14]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:14]#[N:13])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1[nH]c(I)nc1C
Product: CCOC(=O)c1[nH]c(C#N)nc1C
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 1 g 2-Iodo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester in 3 ml pyridine 640 mg CuCN were added and the mixture stirred for 3 h at 110° C. Then the pyridine was removed under reduced pressure and the residue was directly purified by chromatography on silica eluting with DCM/MeOH 97:3. Yield: 494 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:19].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].O>C1COCC1>[O:19]=[C:7]1[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][C:22]3[NH:23][C:24](=[O:25])[NH:1][C:2]=3[CH:3]=2)[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8]1
Reactant: COC(=O)c1ccc2oc(=O)n(Cc3ccc(N)c(N)c3)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1

Procedure:
1.1 g (3.5 mmol) of methyl 3-(3,4-diaminobenzyl)-2-oxo-2,3-dihydrobenzoxazole-5-carboxylate and 626 mg (3.9 mmol) of 1,1′-carbonyldiimidazole are stirred at room temperature for 24 h in 10 ml of THF. The reaction mixture is added to 150 ml of water, and the resultant precipitate is filtered off with suction and dried in vacuo; product; 1.1 g; ESI: 340 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1Cl.C(N(CC)CC)C.[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[NH2:9][C:5]1[N:6]=[C:7]([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:2]([Br:1])=[C:3]([Cl:10])[N:4]=1
Reactant: Nc1nc(Cl)c(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1nc(N)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A stirred solution of 5-bromo-4,6-dichloropyrimidin-2-amine (Reference Example 1, 14.00 g, 0.0576 mole), and triethylamine (41.8 mL, 0.2997 mole) in DMF (55 mL) was treated with tert-butyl 2-aminoethylcarbamate (9.24 g, 0.0576 mole). The reaction mixture was stirred at ambient temperature for 18 hours, then volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid that was triturated with ether to remove color. The ether-insoluble material was collected by filtration and dried under vacuum to provide tert-butyl 2-(2-amino-5-bromo-6-chloropyrimidin-4-ylamino)ethylcarbamate (18.02 g, 85.2% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.42 (s, 9H), 3.25 (t, J=6 Hz, 2H), 3.47 (t, J=6 Hz, 2H). MS (DCl—NH3) m/z=366 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH:7]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:5][CH2:4]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:38][N:3]1[CH2:4][CH:5]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:24]=3)[CH:18]=2)=[O:12])[CH2:7][CH2:8]1
Reactant: CCCCc1nnc(C(=O)NCC2=CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NCC2=CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide dihydrochloride (30 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1 mL), and stirred for 5 min. Sodium triacetoxyborohydride (0.47 mmol, 0.1 g) was added and stirred at room temperature for 2 h. The reaction was diluted with DCM (5 mL), and the DCM layer was separated and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM -6% (NH3 in MeOH, 2M) in DCM to provide 6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1-methyl-1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide, which was converted to dihydrochloride salt by treating with 4 N HCl in dioxane (0.5 mL) in DCM (2 mL). The volatiles were removed under reduced pressure, and the salt was washed with anhydrous ether and solid was dried under high vacuum (38 mg). LCMS: m/z 464.1 [M+1]. 1H NMR (400 MHz, CD3OD): δ 8.38 (1H, s), 7.46 (2H, d), 7.12 (2H, d), 5.71 (1H, s), 4.40-4.50 (1H, m), 4.11 (2H, s) 3.88 (1H, d), 3.55-3.70 (2H, m), 3.17-3.28 (3H, m), 2.94 (3H, s), 2.52-2.66 (1H, m), 2.44 (1H, d), 1.97-2.10 (2H, m),1.75-1.88 (2H, m), 1.25-1.70 (10H, m), 0.84 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=C>ClCCl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[F:15])[CH3:2]
Reactant: C=CCCCCCCCC(=O)OCC
Reactant: C=Cc1ccccc1F
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCC=Cc1ccccc1F
Temperature: 40 °C
Yield: 56.8 %

Procedure:
To a solution of 9-decenoic acid ethyl ester (Tetrahedron 2003, 59, 7973; 500 mg, 2.53 mmol) and 2-fluorostyrene (617 mg, 5.05 mmol) in dichloromethane (12.5 mL) was added dichloro(1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)(phenylmethylene)(tri-cyclohexylphosphine)ruthenium (107 mg, 0.13 mmol). The mixture was flushed with nitrogen and sealed in a pressure tube, then heated at 40° C. for 18 h. After cooling and evaporation of the solvent, the product was purified by chromatography (SiO2, heptane-dichloromethane 3:1) to afford 10-(2-fluoro-phenyl)-dec-9-enoic acid ethyl ester (420 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[N:7]([CH2:16][C:17]([OH:19])=O)[C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][NH:37][C:17](=[O:19])[CH2:16][N:7]3[C:6]4[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=4[N:10]4[CH:12]=[CH:13][CH:14]=[C:9]4[C:8]3=[O:15])[CH2:32][CH2:33]2)=[CH:26][CH:27]=1
Reactant: Cc1ccnc2c1n1cccc1c(=O)n2CC(=O)O
Reactant: COc1ccc(N2CCN(CCCN)CC2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(CCCNC(=O)Cn3c(=O)c4cccn4c4c(C)ccnc43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
2-(1-Methyl-6-oxopyrido[2,3-e]pyrrolo[1,2-a]pyrazin-5(6H)-yl)acetic acid (30 mg, 0.12 mmol), 3-(4-(4-methoxyphenyl)piperazin-1-yl)propan-1-amine (43.6 mg, 0.17 mmol) and DMAP (1.4 mg, 0.012 mmol) were dissolved in 1 mL of DCM. Diisopropylcarbodiimide (0.09 mL, 0.58 mmol) was added. The mixture was stirred at room temperature for 16 hours and the product was purified by silica gel flash chromatography (DCM/MeOH=10:1, Rf=0.5) to give 30 mg (53%) white solid. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=4.9 Hz, 1H), 7.87 (dd, J=1.4, 2.9 Hz, 1H), 7.33 (dd, J=1.4, 4.0 Hz, 1H), 7.12 (s, 1H), 6.99 (d, J=5.0 Hz, 1H), 6.84 (s, 4H), 6.68 (dd, J=2.9, 4.0 Hz, 1H), 5.11 (s, 2H), 3.78 (s, 3H), 3.41 (dd, J=5.8, 12.0 Hz, 2H), 3.02-2.91 (m, 4H), 2.74 (s, 3H), 2.63-2.54 (m, 4H), 2.49 (t, J=6.4 Hz, 2H), 1.75-1.69 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.9, 155.8, 153.8, 145.4, 143.2, 142.3, 134.8, 124.1, 122.8, 122.6, 120.4, 118.0, 114.4, 113.5, 113.4, 57.3, 55.6, 53.4, 50.4, 44.2, 39.4, 25.2, 22.8. HRMS (m/z): calcd for C27H33N6O3 (M+H) 489.2609. found 489.2600.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=1.CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[Cl:10][C:11]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[C:14]([C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])=[CH:13][N:12]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCN(CC)C(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cnc(Cl)cc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
7.62 ml (7.62 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 0.60 g (2.54 mMol) 6-chloro- N,N-diethyl-nicotinamide in 3.0 ml THF cooled to 0° C. The reaction mixture was stirred 2 hours at room temperature, then cooled again to 0° C. and 0.41 ml methanol (10.1 mMol) were added followed by 692 mg 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.1 mMol). After stirring 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure and 50 ml t-butyl-methylether were added at 50° C. The resulting suspension was filtered off, the filtrate was concentrated and the residue was purified by flash chromatography (eluent: ethyl acetate/n-heptane 1:1) to yield 0.67 g (86%) of 6-chloro-N,N-diethyl-4-o-tolyl-nicotinamide as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:31]([OH:33])=O)[CH3:2].Cl.[NH2:35][C@@H:36]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:40]([NH:39][C:37](=[O:38])[C@@H:36]([NH:35][C:31]([C:4]1[N:3]([CH2:1][CH3:2])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([NH:12][C:13]([C:15]1[C:16]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[CH:9][CH:10]=2)=[O:33])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Reactant: CCn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1c(C(=O)N[C@H](C(=O)NCc2ccccc2)c2ccccc2)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h
Yield: 71 %

Procedure:
1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid (0.05 g, 0.11 mmol) and (S)-2-Amino-N-benzyl-2-phenyl-acetamide hydrochloride (0.031 g, 0.11 mmol) were combined in DCM (3 mL) and DIEA (1.1 mL) was added to the above mixture. PyBroP (0.077 g, 0.17 mmol) was added to the above mixture in one portion. The mixture which was resulted was stirred overnight. The crude mixture was then purified by HPLC to furnish the desired product (52.7 mg). HPLC retention time 16.892 min.; Mol. Wt. (calc) 674.7; MS (found) 675.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30](O)=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]([NH2:40])=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(=O)O)(c2ccccc2)OC1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Yield: 46.8 %

Procedure:
A mixture of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, 1.12 mmol), HOBT (302 mg, 2.24 mmol), EDCl (440 mg, 2.24 mmol) and DIEA (1 mL) in anhydrous CH2Cl2 (10 mL) were stirred at 0□ under NH3. Then the solution was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (234 mg, yield 48%). 1H NMR (CDCl3): 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H). LC-MS Method 3 tR=1.3, min, m/z=447, 469; 1H NMR (CDCl3) 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[C:40]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-Trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.2) (0.448 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure III. Obtained as light yellow solid (0.56 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[N:19]=[C:20]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:16][N:17]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 4-aminophenol (1.64 g, 15 mmol) in DMF (40 mL) was added potassium tert-butoxide (1.69 g, 15 mmol) and the resulting mixture was stirred at room temp for 15 min. 4-chloro-2-(trifluoromethyl)pyrimidine in DMF (10 mL) was then added and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified using Biotage flash 40M (2:1, Hexane, Ethyl acetate) to afford 4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (2.2 g, 63%). 1H NMR (DMSO-d6) δ 8.78 (d, 1H), 7.16 (d, 1H), 6.90 (d, 2H), 6.60 (d, 2H), 5.17 (brs, 2H); MS ES 256 (M+H)+, calcd 256, RT=2.42 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([OH:13])=O.Cl.[CH3:15][NH:16][O:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
3-(2,4-Difluoro-phenyl)-acrylic acid (9.5 g, 51.4 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (6.5 g, 66.8 mmol), HOBT (7.6 g, 56.5 mmol), EDAC (10.8 g, 56.5 mmol) and diisopropylethylamine (9.8 mL, 56.5 mmol) were added to dichloromethane (250.0 mL). The reaction mixture stirred at room temperature for 24 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 10.1 g of the titled compound as a yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:29]2=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]2[CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O.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>[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:24]2[C:29]3=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]3[CH:27]=[CH:26][CH:25]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of sodium carbonate (121 mg), tetrakis(triphenylphosphine)palladium(0) (13.18 mg), (4-phenoxyphenyl)boronic acid (98 mg) and 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in DMF (dry) (10 mL) and water (2 mL) was stirred at 80° C. under N2 overnight. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (116 mg) as a white solid. The solid was crystallized from DMSO (1.5 mL)-EtOH (3 mL) to give the title compound (90.7 mg) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CC(=O)CC.[I-].[K+]>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)CCCCCCCl
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)CCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (0.56 g, 4.8 mmol) was added to a solution of 4-bromo-4′-hydroxybiphenyl (0.80 g, 3.2 mmol) in butanone (50 ml) with potassium iodide (0.1 g) as catalyst. This mixture was left stirring at room temperature for 10 min and a solution of 1-chloro-7,7-dimethyloctance from step 6 (0.50 g, 2.8 mmol) in butanone (10 ml) was added dropwise. The reaction mixture was heated under reflux for 44 h. The mixture was filtered and butanone was removed from the filtrate under reduced pressure. The product was extracted into ether (2×75 ml) and the combined ethereal extracts were washed successively with water, 5% sodium hydroxide and water, and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography [DCM] to give a white powder.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>CCCCCC.C(OCC)C>[CH:26]([C:19]1[C:10]([O:9][CH2:8][O:7][CH3:6])=[CH:11][C:12]2[C:13]([CH3:23])([CH3:22])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]=2[CH:18]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: COCOc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
22 ml of a 1.56M solution of n-butyllithium in hexane was dropwise added to 40 ml of a solution of 5.7 g of 5,6,7,8-tetrahydro-2-methoxymethoxy-5,5,8,8-tetramethylnaphthalene in anhydrous diethyl ether at -78° C. The temperature of the mixture was gradually raised to room temperature (in 10 minutes). The resulting mixture was stirred for 5 hours and cooled to -78° C., followed by the dropwise addition thereto of 5 ml of a solution of 2.6 g of N,N-dimethylformamide in diethyl ether. The temperature of the obtained mixture was gradually raised to room temperature (in 10 minutes). The resulting mixture was stirred for 3 hours, followed by the addition thereto of 30 ml of a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 10% ethyl acetate/n-hexane) to give 4.2 g of the title compound as a white solid.