Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55]O)=[CH:50][CH:49]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH2:40]([O:47][C:48]1[CH:49]=[CH:50][C:51]([CH2:54][CH2:55][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]3[C:5]4[C:10](=[N:9][CH:8]=[CH:7][N:6]=4)[N:1]=[CH:2][N:3]=3)=[CH:15][CH:16]=2)=[CH:52][CH:53]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(CCOc3ccc(CCNc4ncnc5nccnc45)cc3)cc2)cc1
Reaction time: 18 h
Yield: 7.3 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (300 mg, 10.1 mmol), triphenylphosphine (790 mg, 3.0 mmol) and 2-(4-benzyloxyphenyl)ethanol (700 mg, 3.0 mmol) were combined in 10 mL anh. dioxane, treated with diisopropylazodicarboxylate (590 μL, 610 mg, 3.0 mmol) and stirred for 18 h. The volatiles were removed in vacuo and the residue was chromatographed on SiO2 with EtOAc (10% to 40%) in CH2Cl2 to obtain (2-{4-[2-(4-benzyloxyphenyl)-ethoxy]-phenyl}-ethyl)-pteridin-4-ylamine (105 mg; 20%) as a white solid: mp 120-122° C.; ESIMS m/z 478 ([M+H]+); 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 6.8-7.5 (m, 13H), 4.1 (m, 2H), 3.90 (m, 2H), 3.01 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH+:8]([O-:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)[CH2:2][CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Pt]>[C:16]([O:13][N:8]1[C:7]([CH3:14])([CH3:15])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:10][C:9]1([CH3:12])[CH3:11])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Agent: [Pt]
Product: CCCOC1CC(C)(C)N(OC(C)=O)C(C)(C)C1

Procedure:
A mixture of 21.4 g (0.1 mol) of 4-propoxy-2,2,6,6-tetramethylpiperidine N-oxide (for preparation, see DE-A-4 219 459) and 11 g (0.108 mol) of acetic anhydride is hydrogenated to saturation at 4 bar over 0.15 g of platinum (10% on carbon). The catalyst is filtered off and the filtrate is diluted with 50 ml of t-butyl methyl ether, washed with cold 12% NaOH solution, 5% HCl and finally water, dried over MgSO4 and freed of the solvent on a rotary evaporator. This gives 18.1 g (70%) of the compound 112 which is in the form of a colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([NH2:12])[CH:4]=1)[CH3:2].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[CH2:9][CH3:10])[NH:11][C:16](=[O:17])[C:15](=[O:19])[NH:12]2)[CH3:2]
Reactant: O=C(O)C(=O)O
Reactant: CCc1cc(N)c(N)cc1CC
Agent: Cl
Solvent: O
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1CC
Temperature: 67.5 °C
Yield: 88 %

Procedure:
4,5-Diethyl-1,2-diaminobenzene (24 ) (459 mg, 2.80 mmol) was dissolved in 4 N hydrochloric acid (12 mL) at 90° C. Oxalic acid dihydrate (983 mg, 6.47 mmoL) was added to this solution in one portion with stirring under N2. The mixture was refluxed at 130-5° C. (oil bath) for 3 h. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo overnight, giving 538 mg (88%) of the title compound 25 as a brown solid; mp>360° C.; 1H NMR (DMSO-d6, 300 MHz) δ 1.092 (t, 6H, J=7.5 Hz), 2.510 (q, 4H, J=7.5 Hz), 6.867 (s, 2H), 11.742 (s, 2H). EIMS m/e 218 (95, M+), 203 (100, M+ --CH3). (HPLC purity 100%)
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(OCCCN3CCCOCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccc(OCCCN3CCCOCC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 7.2 %

Procedure:
4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (900 mg, 26 mmol) was dissolved in THF (5 ml) and cooled to 0° C. under nitrogen. Lithium aluminium hydride (1M in EtO2, 7.8 ml, 78 mmol) was added dropwise and left to stir for 10 minutes before heating to reflux for 18 hours. The solution was cooled to 0° C. before quenching with water (0.78 ml), followed by sodium hydroxide (2M, 0.78 ml) and finally water (2.4 ml). The resulting slurry was filtered through Arbocel®, washing through with DCM (2×10 ml). The filtrate was concentrated in vacuo to afford the title compound as a colourless oil (650 mg, 72%). HRMS ESI+ m/z 349.2480 [MH]+.
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[Cl:14][C:15]1[C:16]([CH3:24])=[C:17]([N:21]=[C:22]=[S:23])[CH:18]=[CH:19][CH:20]=1>C(Cl)(Cl)Cl>[Cl:14][C:15]1[C:16]([CH3:24])=[C:17]([N:21]2[C:4](=[O:13])[CH2:5][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:22]2=[S:23])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: Cc1c(Cl)cccc1N=C=S
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cccc1N1C(=O)CN(c2ccccc2)C1=S
Yield: 33.5 %

Procedure:
A mixture of N-phenyl glycine ethyl ester (8.95 g), 3-chloro-2-methylphenyl-isothiocyanate (9.18 g), and chloroform (200 mL) was heated at reflux for 18 hours. The solvent was evaporated to dryness. The residue was mixed with ethanol (150 mL), and triethyl amine (3 mL). The mixture was heated at reflux for 3 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (300 mL) and washed with 1N HCl (2×200 mL), then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was treated with diethyl ether. The solid was collected by filtration and air dried to give the title compound (5.3 g) as an off-white solid, m.p. 154°-156° C. Anal. Calcd. for. C16H13Cl N2 O S: C, 60.66; H, 4.14; N, 8.84. Found: C, 60.48; H, 4.05; N, 8.76. Mass spectrum (+FAB, [M+H]+) m/z 317/319.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:25][CH3:26])([C:27]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:28])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) and CDI (20 mg, 0.12 mmol) in DMF (1 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (28 mg, 0.3 mmol) and NaH (12 mg, 60%, 0.3 mmol) in DMF (1 mL), which had been stirred for 2 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to “PH” 1-2 by addition of concentrated HCl solution. The aqueous phase was extracted with EtOAc twice, The combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[N:16]=[CH:15][C:14]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[C:13]([O:23][CH3:24])[C:10]=1[C:11]#[N:12].F[C:26]1[N:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][O:23][C:13]1[C:14]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[CH:15][N:16]([C:26]2[C:27]([C:28]#[N:29])=[CH:30][CH:31]=[CH:32][N:33]=2)[C:9](=[O:8])[C:10]=1[C:11]#[N:12]
Reactant: COc1c(-c2ccn(C)n2)cnc(O)c1C#N
Reactant: N#Cc1cccnc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(-c2ccn(C)n2)cn(-c2ncccc2C#N)c(=O)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
A mixture of 2-hydroxy-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)nicotinonitrile trifluoroacetate obtained in Step D (0.20 g), 2-fluoronicotinonitrile (0.710 g), cesium carbonate (0.45 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hr. The reaction mixture was slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent (2 mL) of isopropyl ether/ethyl acetate=1/2, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (0.12 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH:13](O)[C:14](=[CH2:19])[C:15](OC)=[O:16])([O-])=O>C(O)C.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([CH:13]=[C:14]([CH3:19])[C:15](=[O:16])[NH:1]2)=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OC)C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2ccc(N)cc2[nH]c1=O

Procedure:
Methyl 2-[(2,4-dinitrophenyl)(hydroxy)methyl]acrylate was reacted in ethanol in the presence of palladium/carbon under a hydrogen atmosphere to obtain 7-amino-3-methyl-quinolin-2(1H)-one.
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[OH:3].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of the phosphinic acid of Example 20 (0.50 g, 1.1 mmol), methyl bromoacetate (0.2 ml, 2.2 mmol), potassium carbonate (0.24 g, 1.6 mmol) and 2-butanone (20 ml) is heated under reflux overnight. It is then filtered and the filtrate is concentrated to dryness. The crude product is purified by prep. TLC (60% ethyl acetate/hexane) to give methoxycarbonylmethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxyl]ethylphosphinate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17]OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:23]=[N+:24]=[N-:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Dissolved 1-benzyloxycarbonyl-3-methanesulfonyloxymethyl-piperidine (5.24 mmol, 1 eq) in DMF (50 mL). Added sodium azide (1.7 g, 26.2 mmol, 5 eq). Warmed the mixture to 60° C. and let stir overnight. Removed the DMF under reduced pressure. Diluted the residue with ethyl acetate and washed with water and then brine. Dried the organic layer over anhydrous Na2SO4, filtered and concentrated giving 1.27 g. crude product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C(=C/c1cccc2[nH]ccc12)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A suspension of 15.0 g of (Z)-2-ethoxy-3-(1H-indol-4-yl)-acrylic acid ethyl ester in 250 ml of EtOH and 3.08 g of Pd/C (10%) was hydrogenated at 22° C. for 2 h, after which time hydrogen uptake ceased. The suspension was filtered, the filtrate evaporated and the residue chromatographed on silica gel (eluent: gradient of hexane and ethyl acetate) to give 12.28 g of the title compound as a light brown oil.
Reaction SMILES: [F:1][C:2]([F:18])([O:6][C:7]1[N:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].COCCO[AlH2-]OCCOC.[Na+].CC(C)=O.O>O1CCCC1>[F:18][C:2]([F:1])([O:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4]
Reactant: CCOC(=O)c1cccc(OC(F)(F)C(F)F)n1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(OC(F)(F)C(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-(1,1,2,2-tetrafluoroethoxy)-pyridine-2-carboxylate (5.65 g, 21.2 mmol) in tetrahydrofuran (60 ml) was added Red-Al (registered trademark, 6.11 g, 21.2 mmol). The reaction solution was stirred at room temperature for 30 min. and acetone (2 ml) was added. Water (100 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl-acetate=4:1) to give the objective substance (4.2 g, 88%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:29][CH:28]([N:30]([CH3:32])[CH3:31])[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:27][CH:28]([N:30]([CH3:32])[CH3:31])[CH2:29]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Yield: 10.1 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[3-(dimethylamino)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 75) (340 mg, 0.76 mmol) in trifluoroacetic acid (10 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated aqueous ammonium chloride solution (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (30 mg). The combined aqueous washes were extracted with dichloromethane, containing <10% methanol, (3×150 ml). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (180 mg), combined total mass 210 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)c3cccnc3)sc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 59.9 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.52 g, 1.9 mmol) and 4-dimethylaminopyridine (0.07 g, 0.56 mmol) in N,N-dimethylacetamide (10 mL) was added nicotinoyl chloride hydrochloride (0.51 g, 2.86 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.44 g, yield 61%).
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH3:45][C:46]1[CH:55]=[C:54]([NH:56][CH2:57][CH2:58][CH2:59][NH2:60])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C=O)C.C(#N)C>[F:12][C:2]([F:1])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([NH:60][CH2:59][CH2:58][CH2:57][NH:56][C:54]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=[C:46]([CH3:45])[CH:55]=1)=[O:7]
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Reactant: Cc1cc(NCCCN)c2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCCCNC(=O)/C=C/C(F)(F)C(F)(F)F)c2ccccc2n1
Reaction time: 3 h

Procedure:
(E)-4,4,5,5,5-Pentafluoropent-2-enoic acid (38 mg, 0.2 mmol) and HBTU (76 mg, 0.2 mmol) were dissolved in a 1:1 mixture of anhydrous DMF and anhydrous acetonitrile (2 ml), after 5 minutes triethylamine (82 μl, 0.6 mmol) and N-(2-methyl-4-quinolyl)propane-1,3-diamine hydrochloride (48 mg, 0.24 mmol) was added and stirring was continued for 3 hours. To the mixture basic aluminium oxide was added, stirring was continued for one hour, the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 28.4 mg (0.076 mmol, 38%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:13]3[C:18]([CH3:19])=[C:17]([OH:20])[C:16]([CH3:21])=[C:15]([CH3:22])[C:14]=3[O:23][C:11]=2[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccc(C(C)C)cc1
Solvent: CCO
Product: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccc(C(C)C)cc1
Temperature: 0 °C
Yield: 900.7 %

Procedure:
A solution of 2-[1-(4-isopropylphenyl)propyl]-3,5,6-trimethyl-1,4-benzoquinone (1.00 g, 0.324 mmol) in ethanol (1.00 liter) was stirred for 5 hours while cooling it with ice-water to keep the solution at room temperature and while exposing it to light from 400 W Bromcinelight Deluxe (manufactured by LPL Co.). The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain the title compound (0.90 g, yield 90%). This was oily.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C@@H:6]([OH:8])[CH3:7]>[Pd].CO>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C@@H:6]([OH:8])[CH3:7]
Reactant: CC(C)=CCC[C@H](C)O
Agent: [Pd]
Solvent: CO
Product: CC(C)CCC[C@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 866.7 %

Procedure:
5% Palladium on carbon (0.02 g), (2S)-6-methylhept-5-en-2-ol (4.0 g, 3 mmol) and methanol (20 mL) were added to a 50 mL round-bottomed flask fitted with a magnetic stirrer. The flask was evacuated and then pressurised with 1 bar of hydrogen from a balloon. This was repeated three times then the reaction mixture was stirred for 8 hours at room temperature under hydrogen. The crude reaction mixture was filtered and the solvent removed in vacuo to yield (2S)-6-methylheptan-2-ol (3.4 g, 26 mmol, chemical yield 85%), suitable for the next stage.
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1)=[CH2:9])[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>CO>[CH3:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1)[C:3](=[O:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(c1ccc(-c2ccccc2)c(F)c1)C(O)C(=O)OC
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Yield: 73.8 %

Procedure:
To a solution of 1.1 g of metallic sodium in 100 ml of anhydrous methanol was added a solution of 12.2 g of methyl 2-hydroxy-3-(2-fluoro-4-biphenylyl)-3-butenoate in 40 ml of anhydrous methanol, and the resulting mixture was refluxed for 20 minutes and then cooled. The reaction liquid was charged with 10 ml of glacial acetic acid, and the methanol was removed therefrom by distillation at a low temperature and under reduced pressure. The residue was charged with ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. Thereafter, the ethyl acetate was removed by distillation under reduced pressure to obtain 9.0 g of methyl 3-methyl-3-(2-fluoro-4-biphenylyl)-pyruvate. The yield was 73%.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=1)[CH:19]=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:27]([O:26][C:23]([C:24]1[O:22][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:21][C:18]=2[CH:19]=1)=[O:25])[CH3:28]
Reactant: CC(=O)OCCBr
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2o1
Temperature: 120 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a N,N-dimethylformamide (10 mL) solution of 5-benzyloxy-2-hydroxy-benzaldehyde (830 mg, 3.64 mmol) described in Production Example 7-1-2 were added bromoethyl acetate (446 μL, 4.00 mmol) and potassium carbonate (1.01 g, 7.28 mmol) at room temperature, which was stirred at 120° C. for 8 hours. Water was added to the reaction solution at 0° C. followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (890 mg, 83%) as a pale yellow oil.