Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN(C)C(=O)C=C1C(=O)OC(C)(C)O1.C=O.[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[Cl:39][C:40]1[CH:41]=[C:42]([CH:65]=[CH:66][C:67]=1[Cl:68])[CH2:43][N:44]([CH3:64])[C:45]([C:47]1[CH2:51]N(CCC(NCCC(O)=O)=O)[C:49](=[O:62])[C:48]=1[OH:63])=[O:46]>>[Cl:39][C:40]1[CH:41]=[C:42]([CH:65]=[CH:66][C:67]=1[Cl:68])[CH2:43][N:44]([CH3:64])[C:45]([C:47]1[CH2:51][N:25]([CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[C:49](=[O:62])[C:48]=1[OH:63])=[O:46]
Reactant: NCCNC(=O)CCN1CCOCC1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Agent: C=O
Agent: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCNC(=O)CCN2CCOCC2)C1

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and N-(2-amino-ethyl)-3-morpholin-4-yl-propionamide as described in the preparation of Compound 37. The desired product was isolated as a white solid (0.0134 g, 5% yield). 1H NMR (300 MHz, CDCl3) δ: 2.41 (m, 2H), 2.64 (bs, 2H), 2.72 (bs, 2H), 2.98 (m, 2H), 3.03 (s, 3H), 3.51 (t, J=5.6 Hz, 2H), 3.63 (t, J=5.2 Hz, 2H), 3.78 (m, 4H), 4.35 (s, 2H), 4.59 (s, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.35–7.44 (m, 3H), 8.27 (t, 1H). HRMS (M+H) calcd for C22H28N4Cl2O5: 497.13585. found: 497.1377.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:19])[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:22][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([O:19][CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:17][CH3:18])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCC(O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
1-(4′-Trifluoromethyl-biphenyl-4-yl)-butan-2-ol (0.088 g, 0.30 mmol) and 4-hydroxy-benzoic acid ethyl ester (0.062 g, 0.37 mmol) are dissolved in toluene (2 mL) under an inert atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.114 g, 0.45 mmol) is added, followed by tributyl-phosphane (0.1 mL, 0.45 mmol) at 0° C. The reaction is stirred for eighteen hours at room temperature, diluted with ethyl acetate, filtered and concentrated. Column chromatography on silica gel with 0-40% ethyl acetate/hexane gradient gives 0.050 g (0.11 mmol, 38%) of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][S:14][C:15]2[CH:26]=[C:25]([F:27])[C:18]([O:19][CH2:20][C:21](OC)=[O:22])=[C:17]([F:28])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][S:14][C:15]2[CH:26]=[C:25]([F:27])[C:18]([O:19][CH2:20][C:21]([NH2:29])=[O:22])=[C:17]([F:28])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)COc1c(F)cc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Reactant: N
Solvent: CO
Product: NC(=O)COc1c(F)cc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Reaction time: 72 h

Procedure:
Methyl 4-[2-(4-chlorophenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetate (1 g) was added to methanol (50 ml) saturated with ammonia gas, and the mixture was allowed to stand at room temperature for 3 days. The reaction mixture was evaporated under reduced pressure, and the residue was recrystallized from methanol to give 4-[2-(4-chlorophenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (Compound No. 132).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](NCCC3C=CC(OCC(OCC)=O)=C(OCC(OCC)=O)C=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=C[CH:48]=1>ClCCl>[C:17]([C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=2[CH:16]=1)(=[O:18])[CH3:48]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1OCC(=O)OCC
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.67 h
Yield: 191.3 %

Procedure:
To the solution of the compound prepared in (a) (847 mg) in dichloromethane (30 ml) was added Molecular Sieves 4A (3 g), followed by pyridinium chlorochromate (966 mg) under ice-cooling. The mixture was stirred for 40 minutes. After the reaction mixture was filtered through FLORISIL, the filtrate was concentrated to give 772 mg of 2-acetyl-5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (yield, 92%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[CH:13]=2)([OH:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(Br)nc1
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 38.4 %

Procedure:
1.00 g (4.99 mmol) of 1-(6-bromopyridin-3-yl)-ethanone, 1.21 g (4.99 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.42 g of toluene and 0.28 g (1.50 mmol) of tributylamine were fed and the mixture was stirred for 13 hours at 60° C. After cooling the reaction solution to room temperature, the solid was filtered under reduced pressure to obtain 0.85 g of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 38.4%)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:36][NH:37][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCCO)c3)n2)n1
Yield: 43 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.275 g, 0.5 mmol) by treatment with excess ethanolamine in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.110 g, 43%) as a white solid. MS (ISP) 513.9 [(M+H)+]; mp 110° C. (dec.).
Reaction SMILES: [Li+].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2[N:9]=[C:10]([C:12]([O-:14])=O)[S:11][C:5]=2[CH2:4]1.[ClH:15].CN(C)CCCN=C=NCC.O.O[N:29]1[C:33]2C=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1>CN(C)C=O>[ClH:15].[NH2:29][C@@H:33]1[CH2:35][CH2:36][CH2:37][C@H:32]1[NH:31][C:12]([C:10]1[S:11][C:5]2[CH2:4][N:3]([CH3:2])[CH2:8][CH2:7][C:6]=2[N:9]=1)=[O:14]
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3N)sc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.7 %

Procedure:
The compound obtained in Referential Example 61 (175 mg) was dissolved in N,N-dimethylformamide (3 mL), and to the solution were added 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt (90% purity, 258 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (252 mg), 1-hydroxybenzotriazole monohydrate (60 mg), followed by stirring at room temperature for 2 days. The solvent was distilled away under reduced pressure by means of a pump, and the residue was partitioned by adding methylene chloride and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride:methanol=47:3). The resultant pale-yellow oily matter was dissolved in hydrochloric acid-ethanol (5 mL), and the solution was stirred at room temperature for 1 hour. Ethyl acetate was added thereto, and the solvent was removed under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration, to thereby give the title compound (120 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].CCO[C:13]([S-])=[S:14].[K+]>CCO>[Br:8][C:4]1[C:3]2[O:9][C:13]([SH:14])=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cccc(Br)c1O
Agent: [K+]
Solvent: CCO
Product: Sc1nc2cccc(Br)c2o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5 g (26.6 mmol) 2-amino-6-bromo-phenol are dissolved in 20 ml EtOH and 6.52 g (39.9 mmol) potassium ethyl xanthogenate are added. This mixture is stirred for 6 h at reflux temperature. After cooling to room temperature, the reaction mixture is concentrated in vacuo and 50 ml water are added. With the addition of acetic acid, a pH of 5 is adjusted. The product starts to crystallize and is filtered off, washed 2× with water and dried to afford the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([F:15])=[CH:8][N:7]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[F:15][C:9]1[CH:8]=[N:7][C:6]2[O:5][CH2:4][C:3](=[O:2])[NH:12][C:11]=2[CH:10]=1
Reactant: COC(=O)COc1ncc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: O=C1COc2ncc(F)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
In a 250 ml round flask, (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester (1.35 g, 5.87 mmol) and tin tetrachloride (4.45 g, 23.48 mmol) were dissolved in 15 ml of concentrated hydrochloric acid, and then stirred at 80 t for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 10% sodium hydroxide solution, and extracted with ethyl acetate. The combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting solid was recrystallized from tetrahydrofuran and methanol to obtain 7-fluoro-1H-pyrido[2,3-b][1,4]oxazin-2-one as beige solid (0.70 g, 71%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[CH3:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:32]5[CH2:33][CH2:34][CH:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:31][CH2:30]1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1-2
Reactant: CC1CCNCC1
Product: CC1CCN(CCCCC(=O)c2ccc3c(c2)Cc2cc(C(=O)CCCCN4CCC(C)CC4)ccc2-3)CC1

Procedure:
Following the procedure of Example 7, 20.2g (0.05 mole) of 2,7-bis(5-chlorovaleryl)fluorene, prepared in Example 2, and 39.6g (0.4 mole) of 4-methylpiperidine were reacted to give the desired product which was recrystallized three times from chloroform-acetone. M.P. 143°-144.5° C, λmaxCHCl3 329, E1cm1% 731.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
A stirred mixture of 3,4-difluoronitrobenzene (13.5 g, 0.85 mol), methyl 2-(4-hydroxyphenoxy)propionate (23.1 g, 0.085 mol), and potassium carbonate (12.5 g, 0.09 mol) in DMSO (200 ml) was heated in an oil bath (120° bath temperature) for one hour. After cooling the reaction mixture was poured into ice water (1000 ml) and the resulting mixture extracted with ether (3×200 ml). The ether extracts were combined, pentane (200 ml) added, and the resulting solution washed with 5% sodium hydroxide solution (200 ml), then with water. After drying (MgSO4), the solvent was evaporated to give 28 g (98%) of the desired product as a light-yellow oil which solidified upon standing. Recrystallization from hexane-ether gave an analytical sample: m.p.=67.5°-69° C.; Calc: C, 57.31; H, 4.21; N, 4.18. Found: C, 57.00; H, 4.13; N, 4.11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][C@@H:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.[OH-].[Na+].Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][C@@H:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Temperature: 50 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
To a stirred solution of ethyl (S)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (29.20 g, 68 mmol) in dioxane (350 mL) was added aqueous 1.0 N NaOH (110 mL, 110 mmol). The cloudy reaction was stirred at 50° C. in an oil bath for 24 h, then the resulting homogeneous solution was neutralized with aqueous 1.0 N HCl (110 mL, 110 mmol). The solution was concentrated to near dryness by rotary evaporation to precipitate out the product. The supernatant was decanted off and the remaining gummy solid was dried under vacuum and redissolved in 1:1 methanol/CHCl3. The clear solution was then reconcentrated by rotary evaporation and thoroughly dried under vacuum. The remaining solid was triturated with a small volume of water, filtered and dried under vacuum to give the title compound (26.85 g, 94%) as an off-white powder: HPLC (Hamilton PRP-1®, 35% CH3CN/H2O containing 0.1% TFA) k′=2.88; 1H NMR (400 MHz, DMSO-d6) δ7.94 (dd, J=4.7, 1.6 Hz, 1H), 7.38 (m, 1 H), 7.18 (d, J=7.3 Hz, 1H), 7.14 (d, J=3.9 Hz, 2H), 7.08 (m, 1H), 6.97 (d, J=8.4 Hz, 1H),6.83 (d, J=8.6 Hz, 1H), 6.78 (br s, 1H), 6.68 (dd, J=8.3. 2.6 Hz, 1H), 6.50 (d, J=8.3 Hz, 1H), 6.47 (dd, 1H), 4.20 (d, J=14.6 Hz, 1H), 4.00 (t, 2 H), 3.88 (d, J=14.6 Hz, 1 H), 3.67 (m, 1H), 3.37 (m, 1 H), 3.20 (dd, J=1.2, 4.4 Hz, 1H), 2.83 (dd, J=15.2, 10.1 Hz, 1H), 2.60 (dd, J=15.9, 5.3 Hz, 1H), 2.50 (dd, 1H), 1.95 (m, 2 H); MS (ES) m/e 403.3 (M+H)+ Anal. Calcd for C25H26N2O3.H2O: C, 71.41; H, 6.71; N, 6.66. Found: C, 71.21; H, 6.53: N, 6.54.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:27])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH2:28][CH3:29])[C:10]1=[O:30])C1C=CC=CC=1>CO.[Pd]>[CH2:28]([N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:17]([F:27])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:30])[CH3:29]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21
Agent: [Pd]
Solvent: CO
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21
Yield: 72.2 %

Procedure:
Following the procedure of Example 32, hydrogenation of 3-benzyloxy-1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example Y-2, 187 mg, 0.450 mmol) and 10% Pd/C (35 mg) in MeOH (5 mL) afforded 105 mg of the title compound as a solid, mp 219-220° C. (decomp.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]1[CH2:29][CH2:28]1)(=[O:24])[NH2:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=395.2 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH:21]=[CH2:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: C=CCc1cc(Cl)cc2nc(Cc3ccc(OC)c(OC4CCCC4)c3)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(Cl)cc2nc(Cc3ccc(OC)c(OC4CCCC4)c3)oc12
Yield: 45.8 %

Procedure:
A solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chloro-7-allylbenzoxazole (1.2 g, 3.0 mmol) in ethyl acetate (50 ml) was hydrogenated over 0.104 g of 10% Pd on carbon catalyst in a Parr apparatus at 23 psi until hydrogen uptake ceased. The catalyst was filtered and the solvent was evaporated. The residue was recrystallized from hexane to give the title compound (0.55 g, 46%), mp 54-55° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:12](#[N:14])[CH3:13]>C1COCC1.Cl>[CH:3]1([C:8](=[O:10])[CH2:13][C:12]#[N:14])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)C1CCCC1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCC1
Temperature: 70 °C
Yield: 76.7 %

Procedure:
To a suspension of sodium hydride (1.87 g, 55% in mineral oil, 42.9 mmol) in THF (10 ml) was added a solution of methyl cyclopentanecarboxylate (5 g, 39.0 mmol) and acetonitrile (1.92 g, 2.45 ml, 46.8 mmol) in THF (3 ml) dropwise at 70° C. The mixture was heated to 70° C. overnight, then cooled to room temperature, diluted with 1N HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 95:5-85:15) to afford the title compound (4105 mg, 77%) as light yellow liquid.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][C:12]=3[N:3]12.[Br-].[CH2:27]([CH:34]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:37]=[C:36](OS(C(F)(F)F)(=O)=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:27]([CH:34]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:37]=[C:36]([C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:4]4=[N:5][NH:6][C:7](=[O:8])[CH:2]([CH3:1])[N:3]4[C:12]=3[CH:13]=2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1Cc1ccccc1
Reactant: CC1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)C(Cc5ccccc5)C4)cc3N21
Temperature: 90 °C
Yield: 99 %

Procedure:
A mixture of methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (prepared from the corresponding bromide (Preparation #1, Step D) following similar procedure as describe in Example #109, Step B, 0.103 g, 0.3 mmol), tert-butyl 6-benzyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.253 g, 0.6 mmol), Pd(dppf)Cl2—CH2Cl2 complex (0.073 g, 0.09 mmol) and K2CO3 (0.124 g, 0.9 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was heated at 90° C. for 10 h. The reaction was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by PTLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl 6-benzyl-4-(1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.147 g, 99%). LC/MS (Table 1, Method 2) Rt=1.308 min; MS m/z: 489 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:28][C:26]1[CH:27]=[C:22]([NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 54.9 %

Procedure:
Following Example 112a, tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (1.9 g, 5.5 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.47 g, 5.5 mmol), cesium carbonate (5.36 g, 16.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.53 g, 0.55 mmol), Xantphos (0.63 g, 1.1 mmol) and 1,4-dioxane (50 mL) were heated at 100° C. for 8 hours. Work-up and concentrated to dryness. Wash the resulting solid with diethyl ether, filtered and give 56% yield (1.4 g) of 264a as a grey solid: MS (ESI+) m/z 465.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1>O>[N:1]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: C1COCCN1
Solvent: O
Product: CCOC(=O)c1csc(N2CCOCC2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of morpholine (1.5 mL) and ethyl 2-bromo-1,3-thiazole-4-carboxylate (200 mg) was stirred overnight at 50° C. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (193 mg).