Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([NH:25][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Preparation from D-galactose and dodecylamine according to Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[O:17])[C:14]#[N:15])=[N:6][C:7]=1[S:8]([CH2:11]C)(=O)=O.[H-].[Na+]>CN(C=O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16](=[O:17])[CH:13]([C:5]1[N:6]=[C:7]2[S:8][C:11]([NH:1][CH:2]([CH3:3])[CH3:7])=[N:1][C:2]2=[CH:3][CH:4]=1)[C:14]#[N:15]
Reactant: CCS(=O)(=O)c1nc(C(C#N)C(=O)c2ccccc2F)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(5-amino-6-(ethylsulfonyl)pyridin-2-yl)-3-(2-fluorophenyl)-3-oxopropanenitrile (presumed 0.951 mmol, 1.0 eq.) and iPrNCS (0.15 mL, 1.43 mmol, 1.5 eq.) in DMF (4.8 mL) under nitrogen at 0° C. was added NaH (95%; 0.0982 g, 3.89 mmol, 4.1 eq.). After 0.75 hr, the cold bath was removed and the reaction was stirred to room temperature for 0.5 hr. At 0° C., iPrNCS (0.1 mL) and NaH (0.050 g) were added and stirred for 0.25 hr. The cold bath was removed, and the reaction was stirred to room temperature overnight. At 0° C., water and EtOAc were added, and separated. The aqueous layer was washed with EtOAc (2×). The aqueous layer was concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (100:1) as eluent afforded 3-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)-3-oxopropanenitrile as a burgundy solid (0.10 g, 29%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:12]=3)[S:10][C:3]=12.Cl.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][N:33]=1.CC(C)([O-])C.[K+]>CS(C)=O>[NH2:31][C:32]1[N:33]=[CH:34][C:35]([O:38][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:12]=4)[S:10][C:3]=23)=[CH:36][CH:37]=1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)nc4)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 54.3 %

Procedure:
A stirred suspension of 22 (1.0 g, 2.3 mmol), 2-amino-5-hydroxypyridine hydrochloride (405 mg, 2.77 mmol) and potassium tert-butoxide (817 mg, 6.91 mmol) in DMSO (20 mL) under nitrogen was heated to 95° C. for 1 hr then cooled to RT. The reaction mixture was then partitioned between water and AcOEt. The organic layer was successively washed with water, 0.1 N NaOH, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by Biotage (SNAP 50 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV and Silia Flash 80 g; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 27 (634 mg, 1.249 mmol, 54% yield) as pale yellow sticky oil. MS (m/z): 508.6 (M+H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[F:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[C:29]1[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=1>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[O:4][CH2:5][C:6]([OH:8])=[O:7])=[CH:19][C:14]=2[F:13])=[CH:30][N:31]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=C(O)COc1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3OCC(=O)O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)acetic acid and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H14FN3O3, 339.10; m/z found, 339.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=1.4, 2H), 7.71 (d, J=13.3, 1H), 7.51 (d, J=5.7, 2H), 7.29 (dd, J=7.5, 1.7, 1H), 7.25-7.17 (m, 1H), 6.92-6.89 (m, 1H), 6.88-6.80 (m, 3H), 4.14 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH2:27][CH:26]2[C:28](=[O:29])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:21]1[CH2:27][CH:26]2[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=3)([OH:29])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2cccc(Br)c2)C2CCC1CN(Cc1ccccc1)C2
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
1,3-Dibromobenzene (20.2 ml, 167 mmol) in anhydrous ether (100 ml) in a flame dried 1LRB flask, at −78° C. was treated with a 2.5M solution of n-butyllithium in hexanes (58 ml, 145 mmol) via an addition funnel over 20 min. After 1 h at −78° C., the mixture was treated with a solution of 3-benzyl-3-aza-bicyclo[3.2.1]octan-8-one (18.0 g, 83.6 mmol) in anhydrous ether (100 ml) via addition funnel over 20 min. The reaction stirred at −78° C. 30 min, warmed to room temperature and judged complete by TLC. The reaction solution was quenched with saturated aqueous NH4Cl solution (200 ml) and stirred 18 h. The layers were separated and the aqueous layer extracted with ether (2×100 ml). The organic layer was washed with saturated aqueous Na2CO3 solution (150 mL), saturated aqueous NaCl solution (100 ml), dried over Na2SO4, filtered and concentrated to a dark oil. Passage through a silica pad (3×8 in) eluted with 5% EtOAc/hexanes yielded a light yellow oil (31 g, 100%). (TLC 20% EtOAc/hexanes Rf 0.21); 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.41–7.19 (m, 8H), 3.58 (s, 2H), 2.83 (d, J=10.4 Hz, 2H), 2.60 (d, J=8.3 Hz, 2H), 2.35 (br s, 2H), 1.80 (d, J=7.5 Hz, 2H), 1.39 (m, 2H); APCI MS m/z 372.1, 374.1 (M+1)+.
Reaction SMILES: [C:1]([NH:3][C:4](=O)[CH:5](CC)[CH2:6][CH2:7][CH3:8])#[N:2].Cl.[NH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(O)C>[C:1]([N:3]=[C:4]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][CH2:7][CH3:8])#[N:2]
Reactant: CCCC(CC)C(=O)NC#N
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCC(=NC#N)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 100 mg (0.65 mmol) N-cyano-(ethylvaleramidate) (Example 1, Step B , in 2 mL absolute ethanol at room temperature was added 100 mg (0.72 mmol, 1.1 leq) ethyl glycinate hydrochloride followed by 0.30 mL triethylamine (220 mg, 2.16 mmol, 3.3 eq). The mixture was stirred at room temperature overnight then concentrated in vacuo to a gummy residue. The residue was treated with 20 mL of hexane/ethyl acetate (1:1), stirred vigorously, filtered, and the filtrate purified by medium pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (1:1). The title compound (119 mg, 0.56 mmol, 87%) was thus obtained as a pale yellow oil that slowly solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([O:30][C:31](=[O:34])[CH2:32][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(N)=O)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 29 %

Procedure:
(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (3.00 g, 9.87 mmol) was dissolved in DMF (50 mL). To the solution was added potassium carbonate (6.0 g, 39 mmol) and bromoacetic acid tert-butyl ester (6.0 mL, 39 mmol). The solution was heated to 70° C. for 3 h. The reaction was quenched with EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude oil was further purified on a Biotage 40M (loaded in CH2Cl2, eluted in 30% EtOAc/hexanes) to afford a white powder (1.2 g, 35%). MS (ESI), (M+H)+ 446.3; 1H NMR (CDCl3) δ 7.76 (d, 2H, J=8.0), 7.52 (d, 2H, J=8.0), 6.61 (br s, 1H) 5.45 (s, 1H), 4.15-4.18 (m, 1H), 3.09-3.24 (m, 2H), 2.50-2.58 (m, 4H), 2.31-2.39 (m, 2H), 1.92-1.99 (m, 1H), 1.15-1.59 (m, 8H), 1.00-1.04 (m, 7H), 0.71-0.74 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21](=[O:23])[CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH2:26][CH2:27][O:28][C:29]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)=[CH:32][C:30]=3[CH:31]=2)=[O:24])=[CH:18][CH:17]=1)=[O:15])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH2:26][CH2:27][O:28][C:29]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=4)=[CH:32][C:30]=3[CH:31]=2)=[O:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C(=O)OC(C)(C)C)cc2)CCO3)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
In methanol (100 ml) and ethyl acetate (150 ml) was dissolved N-(4-(1-(tert-butoxycarbonyl)piperidin-2-ylcarbonyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (1.0 g), and to the mixture was added hydrochloric acid (17 ml). The mixture was stirred at room temperature for 2 hours, concentrated and neutralized with sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethanol-ethyl acetate-hexane to give N-(4-(piperidin-2-ylcarbonyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 156) (0.6 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[N:3]([CH:24]([CH2:26][CH3:27])[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=2.[CH3:28][Zn]C.CO>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:24]([N:3]1[C:2]([CH3:28])=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[N:7][C:8]=2[C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CCC(C)n1c(C)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Temperature: 65 °C
Yield: 47 %

Procedure:
To a solution of 5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (20 mg, 0.046 mmol), Pd(dppf)Cl2, (3 mg, 8% mmol) in 3 ml of anhydrous dioxane, was added slowly dimethyl zinc (230 μl, 1.0M in heptane solution). The mixture was heated to about 65° C. until in the sealed tube. MeOH was added dropwise and solvents were removed in vacuo. EtOAc was added to the residue and the resulting solution washed with 1 M HCl, water, brine and then dried over Na2SO4. The solvent was removed and the crude mixture was subjected to flash chromatography to obtain 5-(9-sec-Butyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine 8 mg in a yield of 47%. 1H NMR, MeOD: 9.45 (s, 2H); 4.55 (m, 1H); 3.87 (m, 4H); 3.80 (s, 4H); 2.69 (s, 3H); 2.43 (m, 1H); 2.02 (m, 1H); 1.71 (d, 3H); 0.86 (t, 3H). m/z: 369.22 [MH]+.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=1)(=[O:3])[CH3:2].[Br-:24]>C(OCC)(=O)C>[Br:24][CH2:2][C:1]([C:4]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=1)=[O:3]
Reactant: COC(=O)COc1c(C(C)(C)C)cc(C(C)=O)cc1C(C)(C)C
Reactant: [Br-]
Solvent: CCOC(C)=O
Product: COC(=O)COc1c(C(C)(C)C)cc(C(=O)CBr)cc1C(C)(C)C

Procedure:
A mixture of the product from step (i) above (4.91 g) and cuptic bromide (6.82 g) in ethyl acetate (45 ml) was heated at reflux temperature for 24 hours. On cooling, the mixture was filtered and the liltrate concentrated in vacuo. The residue on purification by flash chromatography on silica, eluting with 5% v/v ethyl acetate/hexane, gave methyl 4-bromoacetyl-2,6-di-tert-butylphenoxyacetate, 4.98 g, as an oil: NMR (d6DMSO) δ7.90 (2H, s), 4.92 (2H, s), 4.40 (2H, s), 3.76 (3H, s), 1.41 (18H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(Nc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 4-amino-4′-(trifluoromethoxy)biphenyl (compound of Example 3(2); 112 mg, 0.442 mmol), 4-(tert-butyl)phenylboronic acid (87 mg, 0.486 mmol), copper(II) acetate (40 mg, 0.221 mmol), triethylamine (0.061 ml, 0.884 mmol) and pyridine (3.0 ml) was stirred at 50° for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with 1N hydrochloric acid (10 ml), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (50 mg, 29%) as a pale yellow solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][CH3:31]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:30][CH3:31])[N:10]=[CH:9]1
Reactant: CCBr
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of bromoethane are treated as described in Example 5. The title compound is crystallized in the form of hydrogen oxalate from ethanol and diethyl ether.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:25]([NH:29][C:22](=[O:24])[CH2:21][NH:20][C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[N:16]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)CNc1nc(-c2ccc(F)cc2)cs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 39.9 mg (0.55 mmol) of tert-butylamine. Yield: 15 mg.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([C:14]3[CH:27]=[CH:26][C:17]([CH2:18][N:19]4[CH2:23][C:22](=[O:24])[NH:21][C:20]4=[O:25])=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38]>CN(C=O)C>[N:1]1([CH2:7][C:8]2[N:13]=[C:12]([C:14]3[CH:27]=[CH:26][C:17]([CH2:18][N:19]4[CH2:23][C:22](=[O:24])[N:21]([CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:20]4=[O:25])=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FC(F)(F)CCBr
Reactant: O=C1CN(Cc2ccc(-c3cccc(CN4CCCCC4)n3)cc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccc(-c3cccc(CN4CCCCC4)n3)cc2)C(=O)N1CCC(F)(F)F
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A solution of 1-(4-(6-Piperidin-1-ylmethyl-pyridin-2-yl)benzyl)imidazolidine-2,4-dione (example 134) (120 mg, 0.33 mmol), potassium carbonate (137 mg, 0.99 mmol) and 3-bromo-1,1,1-trifluoropropane (117 mg, 0.66 mmol) in DMF (2.5 ml) was stirred during 17 h at 50° C. After cooling to room temperature the reaction mixture was quenched by the addition of water. The product was extracted into ethylacetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded the title compound (50 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:28][C:29]2[C:30]([CH3:36])=[N:31][N:32]([CH3:35])[C:33]=2[CH3:34])[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([C@H:18]3[CH2:22][O:21]C4(CCCCC4)[O:19]3)[N:14]=2)=[N:10][CH:11]=1.[ClH:37]>C(O)C>[ClH:37].[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:28][C:29]2[C:30]([CH3:36])=[N:31][N:32]([CH3:35])[C:33]=2[CH3:34])[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([C@H:18]([OH:19])[CH2:22][OH:21])[N:14]=2)=[N:10][CH:11]=1
Reactant: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Agent: Cl
Solvent: CCO
Product: COCCSc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2c(C)nn(C)c2C)c1
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A flask was charged with (S)—N-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.200 g, 0.375 mmol), 3M HCl (0.751 ml, 0.751 mmol), and ethanol (5 mL). The reaction was heated to 80° C. for 1 hour and then cooled to ambient temperature. The reaction was concentrated in vacuo and purified using reverse phase chromatography (5 to 95% acetonitrile in water) to afford (S)-1-(5-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.165 g, 0.298 mmol, 79.4% yield) as white solid after HCl salt formation. Mass Spectrum (apci) m/z=453.1 (M+H−HCl).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](=[O:21])[CH3:20])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Br-:22].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>CC(O)=O.Br>[NH2:1][C:2]1[C:3]([C:19](=[O:21])[CH2:20][Br:22])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: [Br-]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(C)=O)n2)CC1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)CBr)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
A solution of 1-(3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-yl)ethanone (510 mg, 1.627 mmol) in AcOH (2 mL) and HBr in AcOH (0.5 mL of 33% w/v, 2.039 mmol) was treated with pyridinium tribromide (544.5 mg, 1.708 mmol) and the mixture allowed to stir at ambient temperature for 2 hours. The reaction was poured into ether (50 mL), partitioned between EtOAc/water and extract with EtOAc (3×). The mixture was dried (MgSO4), filtered, evaporated down and the resultant residue was purified on silica gel by flash column chromatography (0-100% EtOAc/Petrol) to afford the title compound as a orange oil (68 mg, 11% Yield). 1H NMR (400.0 MHz, DMSO) d 1.23 (t, 3H), 3.12 (q, 2H), 3.31 (m, 4H), 3.52 (m, 4H), 4.86 (s, 2H), 7.21 (s, 1H), 8.34 (s, 1H) ppm; MS (ES+) 393.91
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(Cl)Cl>[CH2:23]([N:25]([CH2:26][CH3:27])[C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:2](=[O:1])[C:3]3[C:8]([O:9][C:10]=2[CH:11]=1)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:18])[CH3:24]
Reactant: CCNCC
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
A sample of compound 5a, (13.4 g, 55.6 mmol) was suspended in 220 mL CH2Cl2 and 24.4 mL (330 mmol) of thionyl chloride was added. The mixture was refluxed over 6 h, adding approximately 10 mL of additional thionyl chloride per hour until the reaction became homogeneous. At that time, the thionyl chloride and solvent were removed under vacuum and the remaining residue was diluted with an additional 220 mL CH2Cl2. To the suspension was added 100 mL ice cold 1.5 N NaOH, 100 mL CH2Cl2, and 17 mL (166 mmol) diethyl amine. After stirring for 15 min at room temperature, the phases were separated, and the organic phase was washed with HCl and brine, dried over magnesium sulfate, filtered and concentrated to yield Compound 6a (14.7 g, 49.8 mmol). MS m/z(MH+)296.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][NH:44][C:45]([C:47]1[C:48]([CH3:60])=[N:49][C:50]([CH3:59])=[CH:51][C:52]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:46]>CN(C=O)C>[CH3:43][NH:44][C:45]([C:47]1[C:48]([CH3:60])=[N:49][C:50]([CH3:59])=[CH:51][C:52]=1[N:53]1[CH2:58][CH2:57][N:56]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:55][CH2:54]1)=[O:46]
Reactant: CNC(=O)c1c(N2CCNCC2)cc(C)nc1C
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)cc(C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) was dissolved in anhydrous DMF (1 ml), diisopropylethylamine (52 μl, 0.3 mmol) was added followed by HBTU (60 mg, 0.15 mmol) and the mixture was stirred at room temperature for 15 minutes. N,2,6-trimethyl-4-piperazin-1-yl-pyridine-3-carboxamide (37.2 mg, 0.15 mmol) was dissolved in a mixture of DMF (0.5 ml) and diisopropylethylamine (26 μl, 0.15 mmol) and the resulting solution was added to the solution of the activated carboxylic acid. The resulting mixture was stirred at room temperature for three hours, the solvent was removed under reduced pressure and the raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 21.4 mg of a solid (0.058 mmol, 38%).