Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:25])[C:9]([CH2:21][N:22]([CH3:24])[CH3:23])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CO.O>[CH3:23][N:22]([CH2:21][C:9]1[C:8]([CH3:25])=[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10]=1[CH3:20])[NH:4][CH2:5][CH2:6]2)[CH3:24]
Reactant: CC(=O)N1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
N-(1-Acetyl-5-dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.0 g) was dissolved in MeOH (10 ml) and a solution of NaOH (580 mg) in water (3 ml) was added, which was followed by stirring at 60° C. for 2 hr. MeOH was evaporated under reduced pressure and CHCl3 (100 ml) was added. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure to give 700 mg of N-(5-dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:23](=[O:24])[CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:26][CH3:27])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1Cc1cnc(N)s1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C(=O)Nc1ncc(Cc2cccnc2OC)s1)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (15 mg, 0.041 mmol, 21%). ESI-MS m/z calc. 367.1, found 368.1 (M+1)+ Retention time 3.24 minutes.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=2)=[CH:14][C:13]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH2:39][OH:40].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:28]([O:27][C:25]([C:21]1[CH:20]=[C:19]([C:18](=[N:39][OH:40])[C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:13]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:14]=2)[CH:24]=[CH:23][CH:22]=1)=[O:26])[CH3:29]
Reactant: NO
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CCC(=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc(C(=NO)c2cccc(C(=O)OCC)c2)cc1CCC(=O)OCC
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A mixture of 1.1 g of 2-(decyloxy)-5-[3(ethyloxycarbonyl)benzoyl]benzenepropanoic acid, ethyl ester and 220 mg of hydroxylamine hydrochloride in 25 ml of pyridine was heated at 70° C. for approximately 18 hours. The reaction was allowed to cool to ambient temperature, ethyl acetate was added, and the solution was washed several times with lN hydrochloric acid and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1.04 g of the desired title product as an oil. NMR.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23]CCC(OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[S:13][N:12]=1.CC([O-])(C)C.[K+].Br[CH2:46][CH2:47][O:48][CH3:49].CN(C=O)C>C1COCC1>[CH3:49][O:48][CH2:47][CH2:46][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: COCCBr
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
To a solution of (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-3-ylthio)propanoate (0.420 g, 0.749 mmol) in THF (10 mL) was added potassium 2-methylpropan-2-olate (2.36 ml, 2.36 mmol) and the reaction was stirred at ambient temperature for 5 minutes. 1-Bromo-2-methoxyethane (0.132 g, 0.899 mmol) (as a solution in 2 mL THF) and DMF (1 mL) were added and the reaction was stirred for 20 minutes at ambient temperature. The solution was quenched with water, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (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, 50.1% yield).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Reaction time: 8 h
Yield: 87.5 %

Procedure:
In a round-bottomed flask, 0.88 g of the 3-trifluoromethylheptyl p-toluenesulfonate 2, 0.4 g of ethyl p-hydroxybenzoate and 1 ml of dimethylformamide were placed, and 50 mg of sodium hydride was added thereto, followed by 8 hours of heat-refluxing and 15 hours of standing at room temperature. After the reaction, dimethylformamide was distilled off, and dilute hydrochloric acid was added to the product, which was then extracted with methylene chloride. The resultant organic layer was washed with water and dried with magnesium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography (developer: methylene chloride/ hexane=1/1) to obtain 0.7 g of ethyl p-(3-trifluoromethylheptyloxy)benzoate 3. (Yield: 80%)
Reaction SMILES: C1CO[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:17])[CH2:9][CH2:10][CH2:11][C:12]([O:15][CH3:16])([CH3:14])[CH3:13])([CH3:4])[O:2]1.Cl>CO.O>[CH3:16][O:15][C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]([CH3:17])=[CH:7][CH2:6][CH2:5][C:3](=[O:2])[CH3:4]
Reactant: COC(C)(C)CCCC(C)=CCCC1(C)OCCO1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(C)(C)CCCC(C)=CCCC(C)=O
Yield: 97.7 %

Procedure:
This and the next reaction could be effected with the E and Z isomers or mixtures thereof. A solution of 1.1 g of 2,2-ethylenedioxy-10-methoxy-6,10-dimethyl-5-undecene in 22 ml of methanol containing 11 ml of 0.5N aqueous hydrochloric acid was stirred for 20 hours at room temperature and was then diluted with water and extracted with petroleum ether (b.p.= 40°-75° C.). The extracts were washed with an aqueous sodium bicarbonate solution, then with water and evaporated to dryness to obtain 900 mg of 10-methoxy-6,10-dimethyl-5-undecene-2-one in the form of a colorless oil which was used as is for the next step.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3\[O:11][C:12]([CH3:14])([CH3:13])[C:8]([C:30]4[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=4)=[CH:9]\3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(F)nc1
Temperature: 88 °C

Procedure:
To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (200 mg, 0.62 mmol), 6-fluoropyridin-3-ylboronic acid (104 mg, 0.74 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (2.5 mL, 2.5 mmol). The mixture was heated at 88° C. under N2 for 2 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-5% MeOH/CHCl3 afforded (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 100 mg, 47%.
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=O)[CH:18]=[CH:19][CH:20]=1>>[CH3:2][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:22]=1[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[CH:16]=1)[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: O=C(O)Cc1cccc(Br)c1
Product: CC1=C(Cc2cccc(Br)c2)C(=O)C2C=CC=CC2C1=O
Yield: 52 %

Procedure:
As starting materials for the coupling reaction menadione and 3-bromophenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 328 mg (0.96 mmol, 52% yield) of P_TM99 were isolated as yellow solid.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[N:5][CH:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:39])=[C:34](F)[C:35]=3[F:37])[C:30](=[O:40])[C:29]([C:41]([OH:43])=[O:42])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:39])=[C:34]([N:9]4[CH2:10][CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[N:5][CH:4]=[N:3]5)[CH2:8]4)[C:35]=3[F:37])[C:30](=[O:40])[C:29]([C:41]([OH:43])=[O:42])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: c1ncn(C2CCCNC2)n1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCCC(n4cncn4)C3)c(F)cc2c1=O
Temperature: 90 °C

Procedure:
3-(1,2,4-triazol-1-yl)piperidine hydrochloride (300 mg, 1.59 mmol) and DBU (0.48 g, 3.18 mmol) were added to a suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (180 mg, 0.63 mmol) in acetonitrile (15 ml). The reaction mixture was refluxed at 90° C. for 48 hrs and then concentrated under vacuum. The residue was diluted with water and aqueous solution was extracted with chloroform. The organic layer dried over Na2SO4, concentrated and the residue was diluted with water. The separated solid was filtered and washed with 2 ml of acetonitrile. Yield 13 mg, m.p. 217° C.; 1H NMR (TFA) δ: 9.75 (s, 1H), 9.40 (s, 1H), 8.78 (s, 1H), 8.20 (d, 1H), 5.10 (m, 1H), 4.58 (m, 1H), 3.52-4.40 (m, 4H), 2.55 (m, 2H), 2.20 (m, 2H), 1.30-1.70 (m, 4H).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[C:29]([F:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=1[F:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[Cl:31][C:27]1[CH:28]=[C:29]([F:30])[C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([F:32])[CH:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3c(F)cc(Cl)cc3F)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.30 g (4.57 mmol) of potassium cyanide was added to 1.05 g (2.28 mmol) of the compound from Example 111A in 21 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.74 g (83% of theory) of the target compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cu+2:5].C1COCC1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13]>N1C=CC=CC=1>[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[Cu+2:5].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)[O-]

Procedure:
The method of Kuchen et al. (Angew. Chem. Int. Ed. Engl.), Vol. 27, #12, pp. 1695-1697 (1988) was followed with minor variation. For example, 1.01 g (4.5×10-3 mole) of basic copper carbonate was taken in a 100 ml round bottom flask. A mixture of 50 ml of THF and 2.4 g (0.028 mole) of methacrylic acid was added to it. The system was sonicated for 8 hrs. 30 Milligrams of pyridine was added to get a deep blue solution. The solution can be used directly to prepare the master solution
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1C)[CH3:16]>>[CH2:18]([N:17]([CH2:15][CH3:16])[C:25]1[CH:20]=[CH:21][C:22]([C:10]([C:5]2[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=2[C:7]([OH:9])=[O:8])=[O:11])=[CH:23][CH:24]=1)[CH3:19]
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCn1c(C)cc2ccccc21
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
Homophthalic anhydride (I) can be reacted mol-for-mol with a compound such as 1-ethyl-2-methylindole (T) in the presence of a catalyst, as previously disclosed, to yield keto-acid (II).
Reaction SMILES: [C:1]1([OH:8])[C:5](=O)[C:3](=[O:4])[C:2]=1[OH:7].[CH3:9][C:10]([C:13]1[Se:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19]C2C(Cl)(Cl)C(=O)C=2Cl)[CH:18]=1)([CH3:12])[CH3:11].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>O>[CH3:12][C:10]([C:13]1[Se:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19][C:5]2[C:3](=[O:4])[C:2](=[O:7])[C:1]=2[OH:8])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)[Se]1
Reactant: O=c1c(O)c(O)c1=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C1=CC(=Cc2c(O)c(=O)c2=O)C=C(C(C)(C)C)[Se]1
Temperature: 25 °C
Yield: 94 %

Procedure:
This Example illustrates the preparation, by the reaction D→E shown in FIG. 1, of the squaric acid derivative of Formula II in which Q1 is a 2,6-bis(1,1-dimethylethyl)-4-selenopyrylidene grouping and R1 is a hydrogen atom. 3-[[2,6-bis(1,1-dimethylethyl)-4H-selenopyran-4-ylidene]methyl]-2,4,4-trichlorocyclobut-2-en-1-one (23 g, 52.4 mmole, prepared in Examples 48 and 49 above), trifluoromethane sulfonic acid (80 mL) and water (3 mL) were heated at 105° C. for three hours under nitrogen in a vessel fitted with an outlet connected to a gas-washing bottle containing 10% aqueous sodium hydroxide solution. The resultant dark solution was cooled to room temperature and added slowly to an ice/water mixture with rapid agitation. The resultant red solid was collected by filtration, washed with water and air dried, causing. its color to change to an iridescent green. The crude product so obtained was purified by trituration with cyclohexane for three hours. The pure 3-[[2,6-bis(1,1-dimethylethyl)-4H-selenopyran-4-ylidene]methyl]-4-hydroxycyclobut-3-ene-1,2-dione was collected by filtration, washed with cyclohexane, and dried to afford a red material (18 g, 94% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl[C:15]([O:17][CH2:18][CH2:19][CH2:20][Cl:21])=[O:16].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:20][CH2:19][CH2:18][O:17][C:15]([N:11]1[CH2:10][CH2:9][N:8]([C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: O=C(Cl)OCCCCl
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCCCCl)N1CCN(C(=O)C2CCCO2)CC1
Reaction time: 2 h

Procedure:
To a 0° C. solution of 1-(tetrahydrofuran-2-ylcarbonyl)piperazine (202 mg, 1.1 mmol) in dichloromethane (5 mL) was added 3-chloropropyl chloroformate (133 μL, 1.1 mmol) followed by N,N-diisopropylethylamine (192 μL, 1.1 mmol). The reaction was allowed to reach room temperature over 2 h, at which time the reaction was evaporated to yield the title compound as a wheat colored oil that was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)c1cc(N)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(NC(=O)C(CC(C)C)NC(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-4-methylpentanoic acid (1 g, 3.8 mmol), methyl 5-amino-2-hydroxybenzoate (0.66 g, 3.95 mmol) and Et3N (0.76 g, 7.6 mmol) were dissolved in CH3CN (10 mL) and HATU (1.503 g, 3.95 mmol) was added. The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure. Brine (50 mL) was added to the resulting residue, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed successively with 2N aq. HCl (3×50 mL), brine (50 mL), 5% NaHCO3 (50 mL×3), brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography on (CH2Cl2) to give methyl 5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate as a white solid (0.81 g, 51.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[C:29]([C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1)#[N:30]>>[NH2:12][C:8]1[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:34]([C:31]3([C:29]#[N:30])[CH2:33][CH2:32]3)=[O:35])[CH:28]=[CH:27][CH:26]=2)[C:7]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2cccc(Oc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)c2)CC1
Yield: 42 %

Procedure:
N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide was prepared from 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and 1-cyanocyclopropanecarboxylic acid using Method E (42% yield). HPLC: 96%, RT=4.467 min. MS: m/z=464 [M+H]+, RT=2.24 min. 1H-NMR (DMSO-d6) δ 10.85 (s, 1H), 8.91 (s, 1H), 8.22-8.08 (m, 7H), 7.96 (t, 1H), 7.90-7.87 (m, 4H), 7.63 (d, 1H), 7.54 (broad s, 2H), 3.30 (s, 4H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:15]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][C:7]=1[F:35])[CH3:2].[ClH:37].CO>O1CCOCC1>[ClH:37].[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:15]3[CH2:20][NH:19][CH2:18][C:16]=3[N:17]=2)=[CH:8][C:7]=1[F:35])=[O:36])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OC(C)(C)C)C3)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1F
Yield: 100 %

Procedure:
(S)-tert-butyl 2-(4-(3-ethylureido)-3-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (510 mg, 1.02 mmol) was stirred in a solution of 4M HCl in Dioxane (10 ml), and methanol (3 ml) until analysis by LCMS indicated reaction was complete. Solvent was removed in vacuo to afford a light brown solid (450 mg, 1.02 mmol, 100%).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([C:5]([NH:30][C:31]([O:33][CH3:34])=[O:32])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)C(OCC)=O)[CH3:4].Cl.O>O1CCCC1>[CH2:3]([C:5]1([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[CH2:34][O:33][C:31](=[O:32])[NH:30]1)[CH3:4]
Reactant: CCOC(=O)C(CC)(CCc1ccc(OCCCCc2ccccc2)cc1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CCc2ccc(OCCCCc3ccccc3)cc2)COC(=O)N1
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Lithium borohydride (0.83 g) was added to a solution of ethyl 2-ethyl-2-methoxycarbonylamino-4-(4-(4-phenylbutyloxy)phenyl)butanoate (5.6 g) in tetrahydrofuran (130 ml) and the mixture was refluxed under heating for 4 hours and allowed to stand at room temperature overnight. 2M Hydrochloric acid (11 ml) and water (400 ml) were added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the subject compound (3.0 g).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH:14]([CH3:16])[CH3:15]>>[I:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Oc1cccc2ccc(I)nc12
Product: CC(C)Oc1cccc2ccc(I)nc12
Yield: 84 %

Procedure:
Reaction of 2-iodo-quinolin-8-ol 8 with 2-bromopropane following the method described in Example 8 gave 2-iodo-8-isopropoxyquinoline 9 in 84% yield. 9: 1H NMR (CDCl3): δ 7.75-7.67 (m, 2H), 7.45 (dd, J=7.0 and 8.0, 1 H), 7.33 (dd, J=1.2 and 8.0, 1 H), 7.12 (dd, J=1.2 and 7.0, 1 H), 4.80 (m, 1H), 1.49 (d, J=5.9, 6 H). To a stirred solution of 9 (29 mg, 0.093 mmol) and PdCl2(PPh3)2 (5 mg) in THF (2.5 mL) under an argon atmosphere at RT was added dropwise over 5 min 2-pyridylzinc bromide (0.370 mL of a 0.5 M solution in THF, 0.185 mmol). After 2 h, saturated NH4Cl (5 mL) was added and the mixture extracted with dichloromethane (10 mL×3). The combined extracts were washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. Subsequent column chromatography on silica (dichloromethane/MeOH, 19:1) gave 2-(pyrid-2-yl)-8-isopropyloxyquinoline as a yellow solid. The isopropyl ether was cleaved according to the procedure of Example 8, to give 2-(Pyrid-2-yl)-8-hydroxyquinoline P1 (22 mg, 89%) (data in Table 5).