Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])OC(C(F)(F)F)=[C:3]1[C:19]([O:21][CH3:22])=[O:20].[C:23]([C:27]#[N:28])([Cl:26])([Cl:25])[F:24].C1CCN2C(=NCCC2)CC1.Cl>COCCOC>[Cl:25][C:23]([Cl:26])([F:24])[C:27]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[C:2]([OH:1])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])[N:28]=1
Reactant: N#CC(F)(Cl)Cl
Reactant: COC(=O)c1c(C(C)C)oc(C(F)(F)F)c(C(=O)OC)c1=O
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(C(C)C)nc(C(F)(Cl)Cl)c(C(=O)OC)c1O
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 17.80 g (0.073 mol) of dimethyl 2-(isobutyryl)-3-oxo-1,5-pentendioate (Step B of Example 208) in 300 mL of DME at -78° C. was added 18 g (0.4 mol) of CFCl2CN followed by 11.1 g (11 ml, 0.073 mol) of DBU. The reaction was warmed up to 25° C., poured into 3.7% HCl, and extracted twice with EtOAc. The EtOAc extract was washed again with 3.7% HCl, saturated NaCl and dried (MgSO4). The solvent was removed in vacuo to give 25.88 g of a dark brown solid. The crude was purified by HPLC using 2% HOAc/16% EtOAc/82% cyclohexane as eluting solvent, affording 21 g (81%) of product as a beige solid. For elemental analysis a portion of this solid was washed with hexane affording the product as a white solid: mp 75°-76° C.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C([O:25][C:26](=[O:34])[C@H:27]([CH2:29][CH2:30][C:31](=[O:33])[NH2:32])[NH2:28])(C)(C)C>>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:28][C@H:27]([C:26]([OH:34])=[O:25])[CH2:29][CH2:30][C:31](=[O:33])[NH2:32])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Agent: Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CCC(N)=O)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-glutamine tert-butyl ester hydrochloride using the procedure described in Method 3. The title compound, prepared via cleavage of the tert-butyl ester using trifluoroacetic acid in CH2Cl2, was recovered as a solid, mp=45-55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18]
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Reactant: OCc1cccs1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)cn1Cc1cccs1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 mmoles), thiophenemethanol (0.08 ml, 0.6 mmoles), and triphenylphosphine (197 mg, 0.75 mmoles) was added dropwise diisopropylazodicarboxylate (0.15 ml, 0.75 mmoles) under an atmosphere of nitrogen at 21° C. The reaction mixture was stirred overnight and concentrated under vacuum to give an oil. The oil was chromatographed with silica gel (eluting with 1:4 ethyl acetate/hexane) to give (after crystallization from methanol) 98 mg (56% yield) of the desired 6-(2-thienylmethyl)-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid: mp 141.5°-145.0° C; 1H NMR (CDCl3, 300 MHz) δ5.41 (s, 2H), 6.97-7.56 (m, 9H), 8.78 (dd, 1H, J=8.1, 1.9), 8.93 (dd, 1H, J=4.5, 1.9); 13C NMR (75 MHz, CDCl3) δ161.56, 154.34, 151.68, 137.91, 136.93, 136.79, 134.14, 133.70, 130.04, 129.54, 128.26, 127.81, 127.77, 127.09, 126.65, 122.13, 121.91, 120.05, 46.85; IR (KBr) vmax 1643, 1612, 1591, 1564, 1552, 1483, 1441, 1429, 1415, 1377, 1358, 1302, 1207, 1174, 792, 763, 734, 715, 696, 601 cm-1 ; mass spectrum (EI), m/e 352. Anal. (C19H13ClN2OS) Calcd.: C, 64.68; H, 3.71; N, 7.94. Found: C, 64.45; H, 3.69; N, 8.00.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccccc1Cl
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNCc1ccccc1Cl)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-chlorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=98%, [M+H]+=427.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].Cl>>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 495.3 [(M+H)+]; mp 305° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[OH:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[OH:24])=[O:16])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2
Reactant: CN1CCCc2c(Br)cc(C(=O)O)c(N)c21
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCc2c(Br)cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(N)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (600 mg, 2.10 mmol) in DMF (7 mL) at rt was added (1S,2S)-2-aminocyclohexanol (242 mg, 2.10 mmol), BOP (1.16 g, 2.63 mmol), and Et3N (0.59 mL, 4.21 mmol). The mixture was stirred at rt for 2 h. The resulting solution was quenched with 10% aqueous NaHCO3 and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated to afford 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxamide in pure form.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=O.[CH3:15][N:16]([CH3:20])[C:17]([NH2:19])=[O:18].C(OCC)(=O)C>CN(C)C=O>[CH3:15][N:16]([CH3:20])[C:17]1[O:18][CH:2]=[C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: O=C(CBr)c1cccc2ccccc12
Reactant: CN(C)C(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1nc(-c2cccc3ccccc23)co1

Procedure:
1-(α-Bromoacetyl)naphthalene (5 g) and 1,1-dimethylurea (6 g) were stirred in anhydrous dimethylformamide (20 ml) at 105° C. overnight. The mixture was cooled, added to ethyl acetate, washed with sodium bicarbonate solution, water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound was obtained (0.60 g; m.p. 30-32° C.) following silica gel column chromatography of the residue in dichloromethane.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C@@H:10]([OH:38])[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[CH:19][CH:18]=2)[CH:7]=[CH:6][C:5]=1[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:31]([O:30][C:28](=[O:29])[NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[C:4]([CH2:3][OH:2])[CH:9]=2)[OH:38])=[CH:18][CH:19]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc([C@@H](O)CNCCCCc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)ccc1OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(NCCCCc1ccc(CCCCNC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)cc1)OCc1ccccc1
Temperature: 0 °C
Yield: 64.1 %

Procedure:
A solution of 60 (0.62 g, 0.97 mmol) dissolved in anhydrous tetrahydrofuran (6 as cooled to 0° C. The solution was treated with diisobutylaluminum hydride (4.8 mL, 1M in hexanes). The reaction mixture was allowed to slowly warm to room temperature over 16 h. The solution was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0-20% (10% concentrated ammonium hydroxide in methanol) and dichloromethane to afford the desired product 61 (0.38 g, 64%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.43 (s, 4H), 7.40-7.17 (m, 10H), 7.07 (s, 2H), 6.97 (dd, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 4.78 (dd, 1H), 4.69 (d, 2H), 3.63 (t, 2H), 3.11 (t, 2H), 2.62-2.46 (m, 6H), 1.61 (br, 4H), 1.51 (br, 2H); m/z (ESI) 611 [C38H46N2O5+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23]Cl)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-:26].[Na+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23][I:26])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCCl)C(=O)OC)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCI)C(=O)OC)cc1

Procedure:
A solution of 4.80 g of methyl 2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-5-chloropentanoate of Step 1 and 15 g of sodium iodide in 25 ml of acetone was stirred at room temperature for 3 days. Solvent was removed under reduced pressure, and the residue was washed with water. The product was dried to give methyl 2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-5-iodopentanoate as a pale yellow solid, Electrospray Mass Spec 480.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCc6ccccc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Compound 7B (20 mg, 0.058 mmol) and triethylamine (9.1 μL, 0.064 mmol) were dissolved in dichloromethane (1 mL). Benzyl chloroformate was added to it. The mixture was stirred at room temperature for 2 hours. The crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (18.4 mg, 66.2% yield).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH2:14][N:15]([OH:19])[CH2:16][CH2:17][CH:18]=1)[C:11]#[N:12]>C1(C)C=CC=CC=1>[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH2:14][N:15]([O:19][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH2:16][CH2:17][CH:18]=1)[C:11]#[N:12]
Reactant: CON=C(C#N)C1=CCCN(O)C1
Reactant: CCCN=C=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)ON1CCC=C(C(C#N)=NOC)C1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Propyl isocyanate (0.23 g, 0.00275 moles) was added to a solution of α-(methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (E2) (0.45 g, 0.0025 moles ) in dry toluene (20 ml) with stirring. The mixture was kept at ambient temperature for 2 hrs then evaporated to dryness. The resulting residue crystallised from ethyl acetate/60-80 petrol. Recrystallisation from the same solvent system gave the title compound (E8) as a white crystalline solid (0.37 g, 56%) m.p. 95°-6° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[F:20][C:21]1[S:25][C:24]([NH2:26])=[N:23][CH:22]=1>>[F:20][C:21]1[S:25][C:24]([NH:26][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:23][CH:22]=1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: Nc1ncc(F)s1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ncc(F)s2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 5-Fluoro-thiazol-2-ylamine instead of 3-Chloroaniline to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=333.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:34]1([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH2:52])[CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C=O.C(OCC)(=O)C>[N:34]1([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH:52][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
240 mg of 2-thiophenecarboxylic acid, 390 mg of N,N'-dicyclohexylcarbodiimide and 275 mg of 1-hydroxybenzotriazole were added to a solution of 485 mg of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine in 10 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 17 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate, and the urea which precipitated was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give 499 mg (yield 73%) of the title compound as an oil.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][C:27]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:10]([CH2:18][CH3:19])[CH:11]=2)=[CH:28][CH:29]=1
Reactant: CCc1cc(C(=O)O)ccc1OCC1CCCCC1
Reactant: Nc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCc1cc(C(=O)Nc2ccncc2)ccc1OCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 23-6 (270 mg, 1.0 mmol) in 3.6 mL of CH2Cl2 was added 0.13 mL (1.5 mmol) of oxalyl chloride. The resulting solution was stirred for 1 h, cooled to 0° C. and treated with 380 mg (4.0 mmol) of 4-aminopyridine. Stirring was continued for 1 h before the heterogeneous mixture was diluted with CH2Cl2 and quenched with sat'd NaHCO3. The organic extract was washed with water, brine and dried over Na2SO4. Evaporation of the solvent and column chromatography (3:1 EtOAc/Hexane) afforded product 23-7.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:4](=[O:5])[O:3]1>O1CCCC1.[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]([OH:1])[O:3][C:4]2=[O:5]
Reactant: O=C1OC(O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1C(O)OC2=O

Procedure:
10 g of 3-hydroxy-4-nitro-phthalide are dissolved in 100 ml of tetrahydrofuran and hydrogenated at atmospheric pressure and at 20-35° C. after adding 1 g of palladium on barium sulphate (5%). The catalyst is filtered off and the filtrate is concentrated. The evaporation residue is stirred with ether and filtered with suction. 5.8 g (68.5% of theory) of a colorless substance of melting point 280-285° C. (dec.) are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:11][N:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:45][C:46]([F:58])([F:57])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54](O)=[O:55])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:9]([CH3:18])=[N:10][N:11]=[C:12]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:54](=[O:55])[CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:46]([F:57])([F:45])[F:58])=[CH:52][CH:51]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc([C@H]2CCCN2C(=O)Cc2ccc(C(F)(F)F)cc2)n1Cc1ccc(Cl)cc1
Yield: 91.6 %

Procedure:
(R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole hydrochloride (50 mg, 0.8 mmol) was dissolved in dichloromethane (2 ml). HATU (75 mg, 0.19 mmol), (α,α,α-trifluoro-p-tolyl)acetic acid (37 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.078 ml, 0.45 mmol) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Residue was taken up in EtOAc (20 ml) and washed with saturated solutions of NaHCO3 and NaCl. Organics were dried (NaSO4), filtered and concentrated. Purification by HPLC (water/acetonitrile gradient, 20% to 100% acetonitrile with 0.1% TFA) afforded the desired product as a white amorphous solid (76.3 mg, 91%).
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([O:26][CH3:27])[CH:13]=1)C1C=CC=CC=1.[OH-].[Na+]>CO.O1CCOCC1>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([OH:28])=[O:8])=[CH:13][C:14]=1[O:26][CH3:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(CCC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(CCC(=O)O)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
To a solution of-3-(4-benzyloxy-3-methoxy-phenyl)-propionic acid benzyl ester (11.03 g, 29.30 mmol), in MeOH (110 ml) and dioxane (145 ml), was added dropwise aqueous NaOH 2N (139 ml, 278 mmol). The resulting yellow homogeneous mixture was then stirred at 50° C. for 17 h. The reaction mixture was then concentrated in vacuo and washed with Et2O (100 ml). The aqueous phase was acidified (pH=1) with HCl 2N and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the title carboxylic acid (8.4 g, 29.30 mmol, 100%) as a colorless solid.
Reaction SMILES: [N:1]1[C:2](=[O:9])[NH:3]C(=O)C(=O)C=1.C(O[C:13]([C:15]1([C:40]([O:42]CC)=O)[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[N:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)=[O:14])C.NC(N)=O>[O-]CC.[Na+].C(O)C>[N:35]1([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([O:27][C:24]3[N:23]=[CH:22][C:21]([N:16]4[C:15]5([C:13](=[O:14])[NH:3][C:2](=[O:9])[NH:1][C:40]5=[O:42])[CH2:19][CH2:18][C:17]4=[O:20])=[CH:26][CH:25]=3)=[CH:33][CH:32]=2)[CH:39]=[CH:38][CH:37]=[N:36]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(Cn3cccn3)cc2)nc1
Reactant: O=C1N=CC(=O)C(=O)N1
Agent: CC[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(=O)C2(CCC(=O)N2c2ccc(Oc3ccc(Cn4cccn4)cc3)nc2)C(=O)N1

Procedure:
Following the procedure for pyrimidinetrione formation outlined in Example 1, reaction of 5-oxo-1-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mmol) with urea (0.074 g, 1.2 mmol) in 1.2 mL of 1M sodium ethoxide in ethanol afforded 6 mg of 1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone as a colorless solid. 1H NMR (CD3OD, 500 MHz): 7.99 (d, 1H, J=2.5 Hz), 7.72 (m, 2H), 7.53 (d, 1H, J=2.5 Hz), 7.29 (d, 2H, J=8.5 Hz 7.10 (d, 2H, J=8.5 Hz), 6.97 (d, 1H, J=8.5 Hz), 6.35 (t, 1H, J=2.0 Hz), 5.38 (s, 2H), 2.75 (m, 2H), 2.65 (m, 2H) ppm. MS (APCl, m/z): 447.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:23][N:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 5.6 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyrimidin-2-yl)piperidin-3-ylcarbamate (150 mg, 0.26 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (112 mg, 0.39 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (8.0 mg, 8% over 2 steps) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.33 (br s, 1H), 8.44 (s, 2H), 8.27 (dd, J=8.9, 1.8 Hz, 1H), 8.29-8.19 (m, 1H), 8.04 (d, J=8.9 Hz, 1H), 7.44 (br s, 2H), 4.81-4.71 (m, 1H), 4.48-4.44 (m, 1H), 3.46-3.31 (m, 3H), 2.84-2.77 (m, 1H), 2.23-2.16 (m, 1H), 1.96-1.87 (m, 1H), 1.80-1.60 (m, 2H), 1.21-1.15 (m, 4H); ESI MS m/z 549 [C28H26Cl2N6O2+H]+; HPLC>99% (AUC), tR=11.00 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:33])[O:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH:22]([F:33])[F:21])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1cnc(OC(F)F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3cnc(OC(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(difluoromethoxy)pyrazine-2-carboxylic acid [J. M. Ellard et al. WO2011009898 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=446.5 [M+H]+.