Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH3:6])#[N:2].C(Cl)Cl.C(N)CN.O>C(O)(C(F)(F)F)=O>[C:1]([CH2:3][CH2:4][C@H:5]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH3:6])#[N:2]
Reactant: C[C@H](CCC#N)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CCC#N)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-3-cyano-1-methyl-propyl)-amide (120 mg, 0.223 mmol) was dissolved in a 4:6 solution of TFA:DCM (57 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (134 mg, 2.23 mmol). After stirring at room temperature overnight, water was added and the resulting precipitate was collected by filtration to provide 45 mg (49%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-3-cyano-1-methyl-propyl)-amide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH3:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)cn2ccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Temperature: 23 °C
Yield: 90.9 %

Procedure:
A mixture of 6-bromo-8-methyl-imidazo[1,2-a]pyridine (example C.20 step 1) (7.0 g, 33 mmol), commercially available 4-(trifluoromethyl)phenylboronic acid (6.929 g, 36 mmol), Pd(PPh3)4 (383 mg, 1 mol %) and 1M Na2CO3-solution (77 mL, 77 mmol) in DME (150 mL) was stirred at reflux for 1 h. Cooled to 23° C., diluted with water, extracted with EtOAc, washed the organic layer with brine, dried over MgSO4. Removal of the solvent in vacuum left a brown solid, which was purified by silica gel column chromatography with EtOAc/MeOH to give the title compound as a white solid (8.29 g, 91%). MS (ISP) 277.1 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[CH3:16].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:7]([CH3:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]=1[CH3:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Oc1ccccc1
Yield: 68.6 %

Procedure:
A solution of 4-(3-hydroxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (150 mg), phenylboronic acid (190 mg), copper (II) acetate (189 mg) and TEA (0.22 mL) in dichloromethane (4 mL) was stirred for 6 h. The reaction was diluted into ethyl acetate, washed with 1N hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. The resulting oil was flash chromatographed (10% DEE/petroleum ether) to afford 4-(3-phenoxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (130 mg) as a colorless solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C1C=CC=CC=1>[N:13]1[C:5]2[CH:4]=[CH:3][N:9]=[C:7]([OH:8])[C:6]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC(Cc1ncccc1C(N)=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: Oc1nccc2ncccc12

Procedure:
The product from Example 36c (1.36 g, 6.47 mmol) was dissolved in benzene (35 ml) and to this solution was added pyridinium-para-toluenesulfonate (0.20 g, 0.8 mmol). The mixture was heated to reflux for 23 h then concentrated under vacuum to give the title compound in quantitative yield sufficiently pure for use as isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:21])=[O:20])=[C:4]([NH:9][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:20])=[O:21])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: O=S(=O)(Nc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1

Procedure:
N,N′-(4-chloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (310 mg) was prepared as in Example 31 using 4-chlorobenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride as requisite starting materials.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)=[O:19]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Yield: 90 %

Procedure:
To 3.26 g caesium carbonate and 1.01 g methyl 1-hydroxy-2-naphthoate in 10 ml abs. DMF was added 1.21 g 1-bromomethyl-4-trifluoromethyl-benzene and the mixture was reacted for 3 h at room temperature. The reaction was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate twice. The combined organic phases were dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by chromatography (silica, heptane) to yield 1.62 g of 1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl-].[NH4+].[CH:3]1[C:8]([CH:9]=[O:10])=[CH:7][CH:6]=[C:5]([CH:11]=O)[CH:4]=1.[CH3:13][N:14]1[C:18](=[O:19])[CH2:17][S:16][C:15]1=[S:20]>C(O)(=O)C>[CH3:13][N:14]1[C:18](=[O:19])[C:17](=[CH:11][C:5]2[CH:4]=[CH:3][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)[S:16][C:15]1=[S:20]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CN1C(=O)CSC1=S
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN1C(=O)C(=Cc2ccc(C=O)cc2)SC1=S
Temperature: 110 °C
Reaction time: 12 h
Yield: 72.6 %

Procedure:
A catalytic amount of ammonium chloride was added into 100 ml acetic acid solution containing terephthaldicarboxaldehyde (1.34 g) and 3-methylrhodanine (1.53 g), followed by about 12 hours of heating at 110° C. After cooling upon standing, the formed yellow crystals were collected by filtration, washed with an appropriate amount of ethanol-water (10:1), and dried to obtain 4-(3-methyl-4-oxo-2-thioxothiazolidin-5-ylidenmethyl)benzaldehyde (1.91 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N+:6]=3[O-:30])[C:13]=2[CH:14]=1)#[N:19]
Reactant: CC1(C)C=C(c2ccc(O)cn2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc(O)c[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 7.1 %

Procedure:
400 mg of 4-(5-hydroxy-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 350 mg of m-chloroperbenzoic acid were stirred overnight in 100 ml of dichloromethane. The mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ ethyl acetate for the elution. There were obtained 30 mg of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-hydroxypyridine N-oxide of melting point 260°-262° C. (from ethanol).
Reaction SMILES: O/[C:2](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](/O)\[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.Cl>CO>[CH3:7][O:6][C:4](=[O:5])[C:3]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)=[C:2]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)/C(O)=C(\O)C(=O)OC
Agent: Cl
Solvent: CO
Product: COC(=O)C(Nc1ccc(F)cc1)=C(Nc1ccc(F)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
In a round bottom flask with a teflon stirbar, 25 g (142 mmol) of dimethyl dihydroxyfumarate (prepared according to a procedure described in U.S. Pat. No. 3,334,102), 34.7 g (312.5 mmol) of 4-fluoroaniline, 0.1 mL of concentrated HCl, and 90 ml of methyl alcohol were mixed and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and left overnight in a refrigerator. The next morning, the resulting thick paste was filtered on a coarse frit, washed with a 50% (v:v) methanol-water mixture, and dried in a vacuum oven, yielding 32.4 g (63% yield) which, according to NMR analysis, was a mixture of E/Z isomers (E:Z˜1:2).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][C:11]1([N:29]=[N+:30]=[N-:31])[CH:18]2[CH:14]([O:15]C(C)(C)[O:17]2)[CH:13]([N:21]2[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]2=[O:28])[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)=O.O>[CH2:1]([O:3][P:4]([CH:9]=[CH:10][C:11]1([N:29]=[N+:30]=[N-:31])[CH:18]([OH:17])[CH:14]([OH:15])[CH:13]([N:21]2[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]2=[O:28])[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=CC1(N=[N+]=[N-])OC(n2ccc(=O)[nH]c2=O)C2OC(C)(C)OC21)OCC
Solvent: O
Solvent: O=CO
Product: CCOP(=O)(C=CC1(N=[N+]=[N-])OC(n2ccc(=O)[nH]c2=O)C(O)C1O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 48.4 (130 mg, 0.29 mmol) was dissolved in 90% formic acid in water (2.8 mL). The solution was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was used in the next step reaction without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)=[C:5]([Br:7])[N:6]=1.C[Sn](C)(C)[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=1.[Cl-].[Li+]>O1CCOCC1.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].[Cu]I>[Br:7][C:5]1[N:6]=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[S:3][C:4]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)nc2Br)n1
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(Br)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 25 °C
Yield: 12.1 %

Procedure:
The mixture of 3-(2,4-dibromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (1.10 g, 2.50 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.896 g, 3.00 mmol), tetrakis(triphenylphosphine)palladium (0) (0.155 g, 0.125 mmol), copper(I) iodide (0.143 g, 0.750 mmol) and lithium chloride (0.318 g, 7.50 mmol) in dry 1,4-Dioxane (100 mL) was sonicated for 2 min, degassed and backfilled with nitrogen for 5 times. The mixture was heated under nitrogen atmosphere to reflux for 90 min, cooled to room temperature, filtered thought celite and washed with dioxane/DCM. The filtrate was evaporated under reduced pressure to give a crude residue, which was purified using chromatography on a silica column using MeOH/DCM (0/100 to 5/95) to give a product, which was further purified on a silica column using MeOH/EtOAc/hexane (0/0/100 to 5/45/50) to give pure product (0.150 g, 13%). LCMS: (FA) ES+ 495, 497. 1H NMR (400 MHz, d1-chloroform) 8.72 (s, 1H), 8.37 (m, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.68 (m, 1H), 5.57 (s, 2H), 3.73 (t, J=8.28 Hz, 2H), 2.25 (s, 3H), 0.97 (t, J=8.28 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([CH2:12][N:13]=[N+]=[N-])[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C>CO.[Ni]>[CH:7]1([CH:6]2[CH2:12][NH:13][C:4](=[O:3])[CH2:5]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)CC(CN=[N+]=[N-])C1CCCC1
Agent: [Ni]
Solvent: CO
Product: O=C1CC(C2CCCC2)CN1
Yield: 58.6 %

Procedure:
Preparation of 4-Cyclopentyl-pyrrolidin-2-one—A solution of 3-azidomethyl-3-cyclopentyl-propionic acid ethyl ester (3.7 g, 16.7 mmol) in 50 mL of MeOH is treated with Raney Nickel under an H2 atmosphere at room temperature. When the theoretical amount of H2 is taken up, the catalyst is removed by filtration and MeOH is evaporated. The remaining solid is recrystallized from hexanes to give 1.5 g (58% yield) of 4-cyclopentyl-pyrrolidin-2-one; mp=117-119° C. NMR (1H, 400 MHz, CDCl3) δ1.1 (2H, m); 1.4-1.6 (4H, m); 1.7 (3H, m); 2.1 (1H, m); 2.3 (1H, m); 2.4 (1H, m); 3.05 (1H, dd); 3.4 (1H, dd). Analysis for C9H15NO: Calculated: C,70.55; H,9.87; N,9.14. Found: C, 70.80; H,9.47; N,9.09.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH3:14][NH:15][C@H:16](C(O)=O)[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]12[CH2:3][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:10][CH:11]1[N:15]([CH3:14])[CH:16]([CH3:17])[CH2:13]2
Reactant: C=C(Cl)CN(CC=O)C(=O)OCC
Reactant: CN[C@@H](C)C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(C)C(C)CC2(Cl)C1

Procedure:
10.3 g (50 mmol) of ethyl N-(2-chloroallyl)-N-(2 -oxoethyl)-carbamate are heated under reflux overnight with 5.2 g (50.5 mmol) of N-methylalanine in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:6]1[CH2:7][CH2:8]2)=[O:4]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH2:10][C@H:9]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](c2ccc(O)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Pd(OH)2 on charcoal (20%, 76 mg) was added to a sol. of compound E6 (760 mg, 1.68 mmol) in MeOH (5.00 mL) and THF (5 mL). The mixture was purged with N2, then with H2. The mixture was stirred under an atmosphere of H2 overnight. The mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (590 mg, 97%) that was used further without purification. LC-MS: tR=0.95 min; ES+: 347.36.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14]C(C2CC2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[C:9]=2[F:20])[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[C:9]=2[F:20])[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2ccc(F)c(F)c2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (1 g) prepared as described in Example 1 was dissolved in 10 ml of methanol to prepare a solution. A solution of 0.5 g of sodium hydroxide in 10 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water, and the mixture was neutralized with 1 N hydrochloric acid. The precipitate was then collected by filtration to give 700 mg of 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended in 96 mg of 60% sodium hydride. The 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) (446 mg) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for one hr, 200 mg of acetyl chloride (starting material 2) was then added thereto, and the mixture was stirred at room temperature for 4.5 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 424 mg of 2-ethyl-3-methyl-4-acetyloxy-5,6-difluoroquinoline (compound 12). 1H-NMR data are shown in Table 3.
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: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Reactant: COCCBr
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]decane-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]decane-2-yl)-1,2,4-thiadiazol-5-amine (0.200 g, 50.1% yield).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S1C2C=CC=CC=2N=C1S([CH2:23][C@@H:24]1[NH:28][C:27](=[O:29])[CH2:26][CH2:25]1)(=O)=O.[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([O:53][CH3:54])[N:47]=2)=O)=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>O1CCCC1>[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41](/[C:44](/[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([O:53][CH3:54])[N:47]=2)=[CH:23]\[C@@H:24]2[NH:28][C:27](=[O:29])[CH2:26][CH2:25]2)=[CH:40][CH:39]=1)([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:31])[CH3:32]
Reactant: COc1nc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1Cl
Reactant: O=C1CC[C@H](CS(=O)(=O)c2nc3ccccc3s2)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 17 %

Procedure:
A 1 M solution of lithiumhexamethyldisilazide in tetrahydrofuran (35 mL) was added to a solution of (5R)-5-[(1,3-benzothiazol-2-ylsulfonyl)methyl]pyrrolidin-2-one obtained in Reference Example 3-12 (5.01 g) in tetrahydrofuran (150 mL) at −78° C. in a nitrogen gas stream, and the mixture was stirred at −78° C. for 40 minutes. A solution of (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(5-chloro-6-methoxypyridin-2-yl)methanone obtained in Reference Example 1-28 (3.2 g) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at −78° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=7:3→3:7) to give (5R)-5-[(E)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a colorless oil (688 mg, 17%).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][C:7]=1[OH:13].C([O-])(=O)C.[Na+]>B(F)(F)F.CCOCC>[Cl:5][C:6]1[C:7]([OH:13])=[CH:8][C:9]([OH:10])=[C:11]([C:1](=[O:4])[CH3:2])[CH:12]=1
Reactant: CC(=O)O
Reactant: Oc1ccc(Cl)c(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)c(O)cc1O
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
Acetic acid (17.5 mL) was added dropwise to a suspension of 4-chlororesorcinol (42.5 g, 0.293 mmol) in boron trifluoride etherate (200 mL) under a nitrogen atmosphere. The reaction mixture was heated at 90° C. for 3.5 hours and then allowed to cool to room temperature. A solid had formed after around 1 hour of cooling. The mixture was poured into 700 mL of a 10% w/v aqueous sodium acetate solution. This mixture was stirred vigorously for 2.5 hours. A light brown solid had formed which was filtered, washed with water and air-dried overnight to afford 1-(5-chloro-2,4-dihydroxy-phenyl)-ethanone (31.6 g, 58%). LCMS: [M−H]+ 185.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[Cl:53]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[Cl:53])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(N)c(Cl)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3Cl)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-chloro-benzonitrile according to procedure B followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=414.1 and 416.1 [M+H]+.