Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=1[CH3:19].[CH3:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[NH2:24]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([NH:24][C:23]([CH3:26])([CH3:25])[C:22]([O:21][CH3:20])=[O:27])=[O:18])[CH:13]=[CH:12][C:11]=1[CH3:19]
Reactant: COC(=O)C(C)(C)N
Reactant: Cc1ccc(C(=O)O)nc1Nc1ccc(Cl)cc1Cl
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C)c(Nc2ccc(Cl)cc2Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 4 b, using 6-(2,4-dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 396.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[NH:17][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11]
Reactant: COC(=O)[C@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,6-dichlorobenzoylchloride (0.68 mL) in CH2Cl2 (5 mL) was added to a solution of an ice-cold solution of D-tyrosine methyl ester HCl salt (1.0 g) and DIEA (2.26 mL) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 24 h. The mixture was diluted with CH2Cl2 (50 mL) and washed successively with H2O, 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated, and the residue was recrystallized from EtOAc and hexanes to yield 1.46 g of N-(2,6-dichlorobenzoyl)-D-tyrosine methyl ester. ESMS: m/z 369 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:27])=[O:26].[CH3:33][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:33])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (130 mg, 0.255 mmol) and dimethyl zinc in toluene (0.255 mL, 0.510 mmol), the title compound was obtained as a solid (35 mg, 26% yield). MS (ESI): 489 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1>>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 21 %

Procedure:
Using cyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methanol (0.14 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.15 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.05 g, 31%) was obtained as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:8]([CH2:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15])(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:13]2[CH:8]([CH2:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:15])[CH3:16])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1C2=CC=CCC2C(C)CC1(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C2=CC=C([N+](=O)[O-])CC2C(C)CC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
86.8 g of N-acetyl-2,2,4-trimethyltetrahydroquinoline are dissolved in 600 ml of acetic anhydride and the solution is cooled to 0° C. 28 g of fuming nitric acid in 50 ml of acetic anhydride are now added dropwise. The mixture is kept at 0° C. for a further 30 minutes and is then stirred overnight at room temperature. It is poured onto water and the precipitate is filtered off with suction. 89 g of 1-acetyl-2,2,4-trimethyl-6-nitrotetrahydroquinoline of melting point 91° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6](C(Cl)=O)=[CH:5][CH:4]=1)#[N:2].Cl[Si:13]([CH3:19])([CH3:18])[Si](C)(C)Cl.[C]=O.C[Si](C)(Cl)[Cl:24]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:24][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([SiH:13]([CH3:19])[CH3:18])[CH:5]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(Cl)[Si](C)(C)Cl
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#Cc1ccccc1
Product: C[SiH](C)c1cc(Cl)ccc1C#N
Temperature: 135 °C
Yield: 60 %

Procedure:
A reaction mixture containing 10 gm (6×10-2 mole) of p-cyanobenzoyl chloride and 15 gm (1.25 mole equivalent) of 1,2-dichlorotetramethyldisilane was heated to 135° C. during which time the solution became homogeneous. A cocatalyst mixture containing 200 mg. bis(benzonitrile)palladiumdichloride (1 mole %) and 274 mg triphenylphosphine (2 mole %) was then introduced. Carbon monoxide gas evolution began immediately and the reaction was heated at 140° C. for 12 hours while dimethyldichlorosilane was continuously removed. Vacuum distillation gave 7 gm (60% isolated yield) of 4-chlorodimethylsilylbenzonitrile, bp. 93°/0.1 torr, m.p. 40°-43° C. The resulting chlorodimethylsilylbenzonitrile, in the form of a low melting high moisture sensitive solid was hydrolyzed to the corresponding 1,3-bis(4'-benzonitrile)tetramethyldisiloxane in the form of a colorless liquid. The identity of the disiloxane was further confirmed by its NMR and IR spectra.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Na+:11].[Cl-].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:13]([O-:16])(=[O:15])=[O:14])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Na+:11]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)([O-])c1ccc2c(c1)NCCC2
Temperature: 100 °C

Procedure:
1,2,3,4-tetrahydroquinoline was added dropwise to 40 mL fuming sulfuric acid at 0° C. over 15 minutes. This mixture was then heated to 100° C. for 1 hour with stirring. After cooling to 0° C. saturated NaCl (aqueous) was added drop wise, precipitating the crude product as a white solid. The solid was washed, first with cold isopropanol, followed by diethyl ether, then dried under vacuum to give the desired product as a white solid. 1H-NMR (300 MHz, d6 DMSO): δ 7.43 (m, 2H), 7.21 (d, 1H), 3.38 (m, 2H), 2.81 (t, 2H) 1.96 (m, 2H) ppm; MS m/z calculated for C9H10NO3S (M−): 212.04. Found 212.0 (M−, ESI−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[H-].[Na+].Cl[CH:15](Cl)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][CH:15]([C:16]([O:18][CH3:19])=[O:17])[O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1Oc2ccc([N+](=O)[O-])cc2O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
31.0 g of 4-nitrocatechol was added to 17.6 g of 60% NaH in suspension in 300 ml of DMF over 1 hour, with cooling to keep the temperature below 30° C. Stirring was continued for 15 minutes then 104 ml of methyl dichloroacetate was added over 1 hour, and stirring was continued for 4 hours at 90° C. The reaction medium was poured over a mixture of 2 liters of ice/water then extracted 4 times with 400 ml of AcOEt. The combined organic phases were washed once with a saturated NaCl solution then dried and concentrated under vacuum (DMF evaporated off). The residue was taken up in a AcOEt/H2O mixture and the pH was brought to 8.6 using Na2CO3; the organic phase was decanted, washed with saturated NaHCO3, H2O, 5% KHSO4/K2SO4, H2O, saturated NaCl then dried and vacuum evaporated; a semi-solid residue was obtained which was taken up then triturated in heptane to produce a solid. m=27.7 g, MP=90-92° C.
Reaction SMILES: [CH:1]([O:14][N:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18](=[O:31])[CH:17]=[C:16]1[CH2:32][N:33]1C(=O)C2C(=CC=CC=2)C1=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(Cl)(Cl)Cl.CO>[NH2:33][CH2:32][C:16]1[N:15]([O:14][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:18](=[O:31])[CH:17]=1
Reactant: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN3C(=O)c4ccccc4C3=O)cc2=O)cc1
Agent: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-((1-(benzhydryloxy)-5-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl)isoindoline-1,3-dione (Intermediate 292, 1.66 g, 2.90 mmol) in chloroform (20 mL) and methanol (10 mL) at room temperature was added hydrazine monohydrate (0.284 mL, 5.80 mmol). The reaction mixture was stirred overnight at room temperature. Another 1 eq of hydrazine monohydrate was added. After 3 hours still see starting material. Added another 1 eq of hydrazine monohydrate. After 2 hours the reaction mixture was filtered to remove solids. The filtrate was concentrated. The residue was triturated with MeOH and ether and the solids filtered off. This was repeated twice more. The resulting solid was triturated once with chloroform and MeOH and the solids removed by filtration. The filtrate was concentrated to afford a yellow foam (1.01 g, 79%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C([O-])(O)=O.[Na+].C(O[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C>>[C:19]([O:8][C:7]([C@H:2]1[NH:1][C:5](=[O:6])[CH2:4][CH2:3]1)=[O:9])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of L-pyroglutamic acid (2.00 g, 15.49 mmol) in t-butyl acetate was added 70% HClO4 (0.46 mL, 17.04 mmol). The suspension was stirred at rt in a tightly closed flask overnight. The resulting solution was poured slowly into a sat. solution of NaHCO3 and extracted twice with EtOAc. The organic phase was dried over MgSO4 and concentrated to provide (S)-pyrrolidin-2-one-5-carboxylic acid t-butyl ester. (2.04 g, 85%) as a white solid 1H NMR (CDCl3) δ 1.48 (s, 9H), 2.16-2.48 (m, 4H), 4.14 (m, 1H), 5.97 (bs, 1H). MS calcd for C9H15NO3 +H 186, found 186.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[C:5](=[O:10])[CH2:6][C:7](=[O:9])[CH3:8])[CH2:2][CH3:3].CC(O[Na])=O.O.[Cl-].[C:21]1([N+:27]#[N:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:11]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:10])[C:6](=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7](=[O:9])[CH3:8])[CH2:12][CH3:13]
Reactant: CCCN(CCC)C(=O)CC(C)=O
Reactant: N#[N+]c1ccccc1
Agent: CC(=O)O[Na]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C(=O)C(=NNc1ccccc1)C(C)=O
Yield: 14.5 %

Procedure:
18.5 g (0.1 mol) of N,N-dipropyl-3-oxobutyramide, 12 g (0.146 mol) of CH3COONa, 20 ml of water, 75 ml of ethanol and a solution of 0.1 mol of phenyldiazonium chloride were treated as described in preparation 2. The precipitated solid was filtered and dried in vacuo yielding 4.2 g of the title compound. M.p.=79°-80° C.
Reaction SMILES: [CH3:1][C-:2]1[C:6]([CH3:7])=[C:5](C)[C:4]([CH3:9])=[C:3]1[CH3:10].[C-]1([C:16]([N:18]=[N+]=[N-])=[O:17])C=CC=C1.[Fe+2:21].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH3:7][C-:6]1[CH:5]=[C:4]([CH3:9])[C:3]([CH3:10])=[C:2]1[CH3:1].[C-:4]1([CH2:9][C:16]([NH2:18])=[O:17])[C:3]([CH3:10])=[CH:2][CH:6]=[CH:5]1.[Fe+2:21]
Reactant: [N-]=[N+]=NC(=O)[c-]1cccc1
Reactant: Cc1c(C)c(C)[c-](C)c1C
Agent: [Fe+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1c[c-](C)c(C)c1C
Product: Cc1ccc[c-]1CC(N)=O
Yield: 162.8 %

Procedure:
0.13 g (0.4 mmol) of 1′,2′,3′,4′,5′-pentamethylferrocene-1-carboxylic acid azide are stirred with 0.5 ml of acetic acid in 10 ml of acetic anhydride at 80° c for five hours. Aqueous work-up gives 0.102 g of 1′,2′,3′,4′,5-pentamethylferrocen-1-yl-acetamide.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.ClN1C(=O)CC[C:29]1=O.C[Sn](C)(C)C>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.C1(C)C(C)=CC=CC=1>[CH3:11][C:9]1([CH3:12])[O:8][C:7]2[C:2]([CH3:29])=[CH:3][C:4]([F:26])=[C:5]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[C:6]=2[O:10]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c3c2OC(C)(C)O3)c1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)C
Solvent: Cc1ccccc1C
Product: Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c2c1OC(C)(C)O2
Temperature: 120 °C

Procedure:
Synthesis of this compound starts with 3-(7-bromo-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)-1-methyl-6-trifluoromethyluracil (Compound 17) which may be synthesized using the methods of Example 1, Steps F through H, by substituting N-bromosuccinimide for N-chlorosuccinimide in Step F. In a tube are placed 2.2 g (0.005 mole) of 3-(7-bromo-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil, 0.95 g (0.0053 mole) of tetramethyl tin, 0.05 g (0.00005 mole) of tetrakis(triphenylphosphine)palladium(0), and 3 mL of xylene. The tube is sealed and heated at 120 ° C for approximately 20 hours after which it is cooled, the seal is broken, and the contents are removed. The reaction mixture is passed through a column of silica gel, eluting with heptane/ethyl acetate ( 1:1 ). The product-containing fractions are combined, and the solvent is evaporated under reduced pressure, yielding 3-(2,2-dimethyl-5-fluoro-7-methyl- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil as the residue.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.[CH3:22][N:23]1[CH2:29][C:28]2[CH:30]=[C:31](/[CH:34]=[CH:35]/[C:36](O)=O)C=N[C:27]=2[NH:26][C:25](=O)[CH2:24]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:26]([CH3:27])[CH2:25][C:24]2[N:23]([CH3:22])[C:29]3[C:35]([CH:36]=2)=[CH:34][CH:31]=[CH:30][CH:28]=3)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCCCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(CN2CCCCC2)c1
Yield: 54 %

Procedure:
According to the procedure of Example 1 (a), except substituting (E)-3-(6-amino-5-piperidin-1-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (294 mg, 54%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.78-7.68 (m, 1H), 7.49-7.38 (m, 3H), 7.14-6.97 (m, 3H), 6.63 (s, 2H), 6.41-6.18 (m, 1H), 5.02-4.83 (m, 21), 3.72-3.67 (m, 3H), 3.39-3.34 (m, 3H), 3.09-2.96 (m, 3H), 2.29 (br s, 3H), 1.49-1.40 (m, 6H); MS (ESI) m/e 418 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)CCC>CN(C=O)C.C(OCC)(=O)C.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>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cnccn3)ccc1Oc1c(F)cc(O)cc12
Temperature: 110 °C

Procedure:
Pd(PPh3)4 (0.506 g, 0.438 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (1.6 g, 4.38 mmol), and 2-(tributylstannyl)pyrazine (2.426 g, 6.57 mmol) were combined in 10 ml of DMF and heated in the microwave at 110° C. for two hours. The solution was diluted with ethyl acetate (50 mL) and washed twice with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified via silica gel column chromatography (RediSep 40 g column) using 10-100% 90/10/1 (CH2Cl2/MeOH/ammonia) in CH2Cl2 to afford (S)-2-amino-4′-fluoro-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a white solid. MS m/z=365.0 [M+H].
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][S:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:22][C:23]([F:34])([F:33])[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25]>O.C(OCC)(=O)C>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[S:9][CH2:8][CH2:7][NH:32][CH:29]1[CH2:28][CH2:27][N:26]([C:24](=[O:25])[C:23]([F:22])([F:33])[F:34])[CH2:31][CH2:30]1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Reactant: BrCCSc1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N1CCC(NCCSc2cccs2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.14 g of 2-(2-bromoethylthio)thiophene, 95 mg of potassium carbonate and 0.16 g of 1-(trifluoroacetyl)piperidine-4-amine hydrochloride were added under cooling with ice, and the mixture was stirred at room temperature for 40 minutes. Thereto was added 95 mg of potassium carbonate under cooling with ice, and the mixture was stirred for 45 minutes, and stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1] to obtain 62 mg of a yellow oily substance, N-(2-(2-thienylthio)ethyl)-1-(trifluoroacetyl)piperidine-4-amine.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)NCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A solution of N-acetylethanolamine (10.0 g, 6.79 ml, 97 mmol) in a mixture of anhydrous tetrahydrofuran (100 ml) and dimethylformamide (10 ml) was added to a stirred suspension of 80% sodium hydride in oil dispersion (2.90 g, 97 mmol) in dry tetrahydrofuran (140 ml), under nitrogen, at room temperature. After 1 hour, the reaction mixture was heated to 40°-50° C. and then, after a further 0.5 hour, cooled to ice-bath temperature. Next, benzyl bromide (13.8 ml, 116 mmol) was added and the resulting suspension stirred at room temperature for 18 hours, before being cautiously quenched with water (400 ml). The resulting mixture was extracted with ethyl acetate (2×300 ml) and the combined extracts washed with water (200 ml), dried (Na2SO4) and evaporated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water, then the organic phase washed thrice with water, dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of methanol:ethyl acetate (0:100 to 10:90), to give the required product (7.8 g) as an oil. Rf 0.21 (SS 17). LRMS: m/z 194.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[N:15]=[C:14](F)[CH:13]=[C:12]([F:17])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[CH:13]=[C:12]([F:17])[N:11]=[C:10]([F:9])[N:15]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(F)nc(F)n1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1cc(Nc2ccc(Cl)cc2)nc(F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloroaniline was added to a stirred solution of 2,4,6-trifluoropyrimidine (7.7 g), potassium carbonate (7.86 g) in ethanol (80 ml). The mixture was stirred at room temperature for 16 h, diluted with water, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (4:1). Yield 8.3 g cream solid
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]1=[O:16].[CH2:17]([NH2:19])[CH3:18]>>[CH2:17]([NH:19][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][C:3](=[O:16])[N:2]([CH3:1])[C:7]=2[N:8]=1)[CH3:18]
Reactant: Cn1c(=O)ccc2cnc(S(C)(=O)=O)nc21
Reactant: CCN
Product: CCNc1ncc2ccc(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A mixture of 8-methyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (152 mg, 0.63 mmol) in 2.5 mL of 70% aqueous ethylamine was stirred at room temperature for 10 minutes. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated in vacuo to give 105 mg (82%) of 2-ethylamino 8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 194-195° C.