Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])[N:3]=1.[NH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:28]1[CH2:27][CH2:26][CH:25]([CH2:24][NH:23][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH2:30][CH2:29]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
(4-Chloro-5-cyanopyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (50 mg, 0.16 mmol) was dissolved in DMF (1 mL) and tert-butyl trans-4-aminomethylcyclohexylcarbamate (70 mg, 0.30 mmol) was added followed by DIPEA (53 μL, 0.30 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with EtOAc and washed with water (×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 76 mg (96%) of (4-{[5-cyano-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][N+:21]=1[O-:30])[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:31]([OH:33])=[O:32])[NH2:8])=[N+:21]([O-:30])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)c[n+]1[O-])C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](C[C@H](Cc1ccc(OCCF)c[n+]1[O-])C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 170 mg of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(2-fluoroethoxy)-1-oxidopyridin-2-yl]methyl}-L-glutamate (0.32 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (124 μL, 5 eq) and the mixture was stirred for 2 h at room temperature. LC/MS revealed substantial quantities of starting material were present; hence an additional 5 eq of trifluoroacetic acid were added and stirring at room temperature was continued overnight. Repeated LC/MS still showed incomplete removal of the protecting groups. The mixture was evaporated, re-dissolved in trifluoroacetic acid and dichloromethane (2 mL each) and stirred at room temperature for another 2 h, whereupon the reaction was complete. The mixture was evaporated and the residue was purified by preparative HPLC (Method E), followed by lyophilisation to give 95 mg of the target compound as light brown lyophilisate in approx. 90% purity (84% purity adjusted yield).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:13]([CH3:21])([CH2:15][CH2:16][C:17](Cl)([CH3:19])[CH3:18])[CH3:14]>ClCCl>[CH3:14][C:13]1([CH3:21])[CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:9]2[CH:10]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]1=2
Reactant: Oc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 32.5 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Aluminum trichloride (25 g, 0.18 mol) was added portions to a solution of phenol (49.5 g, 0.52 mol) and 2,5-dichloro-2,5-dimethylhexane (101.0 g, 0.55 mol) in dichloromethane (700 mL). The reaction mixture was allowed to stir at 25-40° C. for 2 h, then the dark red mixture was poured onto ice water. Aqueous work up (EtOAc extraction) gave 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol 84.8 g (80%) as a white solid, which was recrystallized from hexane to give the product as colorless needles: 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 1H, ArH), 6.78 (d, 1H, ArH), 6.62 (dd, 1H, ArH), 4.55 (s, 1H, OH), 1.65 (s, 4H, 2CH2), 1.25 (s, 12H, 4CH3).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N+:31]=2[O-:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(NCCN2CCCCCC2)nc2cc3c(cc21)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(NCCN2CCCCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.7 %

Procedure:
H2O2 (70%, 0.37 mL, ca. 7.3 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 7.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 46 (240 mg, 0.7 mmol) and TFA (0.28 mL, 3.7 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 47 (146 mg, 61%) as a red solid: mp (MeOH) 181-184° C.; 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.55 (br s, 1H, NH), 3.56-3.60 (m, 2H, CH2N), 3.03-3.07 (m, 4H, H-6, H-8), 2.81 (dd, J=6.1, 6.0 Hz, 2H, CH2N), 2.67-2.72 (m, 4H, 2×CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.60-1.71 (m, 8H, 4×CH2); 13C NMR δ 155.6, 149.4, 145.7, 138.0, 129.6, 115.7, 111.5, 55.9, 55.1 (2), 39.0, 33.4, 32.3, 28.5 (2), 27.0 (2), 25.5. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.9; H, 7.2; N, 20.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]=1[O:20][CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:6].[CH:28](Br)(C)C.NC1C=CC(C(OC)=O)=C(C)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]=1[O:20][CH:21]([CH3:22])[CH3:23])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:15]([CH3:28])[CH:16]=1)=[O:6]
Reactant: CC(C)Br
Reactant: CC(C)Oc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(Cl)c1OC(C)C
Agent: COC(=O)c1ccc(N)cc1C
Product: Cc1cc(NC(=O)c2cc(Cl)c(OC(C)C)c(OC(C)C)c2)ccc1C(=O)O

Procedure:
4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-051) (103 mg, 48% for final step) was prepared in essentially the same manner as AAA-044 except isopropyl bromide was used instead of cyclopentyl iodide and the reaction performed at 80° C. in step (iii) and that methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (v): m/z 404 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.62 (1H, br s), 10.34 (1H, s), 7.87 (1H, d), 7.73 (1H, dd), 7.68 (2H, d), 7.54 (1H, d), 4.76 (1H, m), 4.59 (1H, m), 2.54 (3H, s), 1.33 (6H, d), 1.28 (6H, d).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of ethyl {4-[(butyl{5-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)methyl]-2-methylphenoxy}acetate (190 mg, 0.37 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was added 2M sodium hydroxide (4 mL). The resulting mixture was stirred at room temperature for 2 h. The solvents were removed in vacuo and the residue was diluted with water (20 mL), acidified with 2M HCl and extracted ethyl acetate (50 mL). The organic solution was washed with brine (20 mL), dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as a white foam (180 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].F[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
Glycine (5.31 g, 70.8 mmol) was added to a mixture of 1-fluoro-4-nitro-benzene (5.0 g, 35.4 mmol) and sodium bicarbonate (5.94 g, 70.8 mmol) in dioxane (10 mL) and water (60 mL) and heated at reflux for 6 h. The reaction mixture was cooled to room temperature and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid to pH ˜3 and extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to dryness to afford (4-nitro-phenylamino)-acetic acid (5.0 g, 72%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)C.[OH-].[Na+].Cl>O>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:21])=[O:3])[CH:11]=[CH:10][C:9]=1[OH:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(O)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(O)c(OCc2ccccc2)c1
Yield: 88.5 %

Procedure:
5.35 g of the ester obtained above was added to a mixture of 50 ml of water and 1.49 g of sodium hydroxide. The resultant solution was refluxed for 2.5 hours, acidified with concentrated hydrochloric acid and evaporated under reduced pressure to give solids, which were purified by Soxhlet extraction apparatus to provide 4.27 g(yield 89%) of the desired compound as a yellow solid, having the characteristics of: m.p. 130°-133° C.; NMR(CDCl3, 200 MHz) δ3.45(s, 2H, CH2Ar), 5.09 (s, 2H, OCH2), 6.75-7.40(m, 6H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[Cl:20])=[CH:4][CH:3]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.2 %

Procedure:
A stirred solution of 38.0 grams (0.136 mole) of diethyl (4-chlorophenyl)hydroxymethylphosphonate in 250 ml of methylene chloride was cooled to 0° C., and a solution of 18.8 grams (0.158 mole) of thionyl chloride in 12 ml of methylene chloride was added via syringe. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 60 hours. After this time the reaction mixture was washed with two portions of aqueous 1N hydrochloric acid. The organic layer was filtered through silica gel. The silica gel was eluted with 1:1-hexane/ethyl acetate. The combined filtrates were concentrated under reduced pressure, yielding 40.5 grams of diethyl (4-chlorophenyl)chloromethylphosphonate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:16])=[C:7]([NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:16])=[C:7]([NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH:8]=1
Reactant: CCCS(=O)(=O)Nc1cc(OC)ccc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To the solution of propane-1-sulfonic acid (5-methoxy-2-methyl-phenyl)-amide. (97 mg, 0.38 mmol) and CH2Cl2 (3 mL) at 0° C. was added dropwise boron tribromide (0.75 mL, 1M in CH2Cl2). The reaction mixture was stirred at 0° C. for 1 h then at RT for 1.5 h. The mixture was washed with H2O and sat. NaHCO3, extracted with CH2Cl2, dried over Na2SO4 and concentrated to give the product as a clear oil (47.1 mg, 54%): MS(ES) m/e 230.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].[H-].[Na+].C([Li])(CC)C.C1CCCCC1.Cl.[C:27](=O)(O)[O-:28].[Na+]>CN(C)C=O.O1CCCC1>[CH:27]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12])=[O:28]
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
5-Bromo-1H-indole-3-carbonitrile (4.25 g, 19.23 mmol) and sodium hydride (0.51 g, 21.2 mmol) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (24 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to −78° C. and a solution of sec-butyllithium in cyclohexane (1.4M, 30.2 mL, 2.2 equiv) was added over several minutes. After 1 h at −78° C., dimethylformamide (6.0 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0° C. and carefully treated with 1 N hydrochloric acid (45 mL). After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography gave 2.4 g (72%) of pure material. LC/MS: tR=0.99 min, 171.07 (MH)+.
Reaction SMILES: [CH:1](/[C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: Nc1nc2ccccc2c2cc(/C=C/c3ccccc3)cnc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc2ccccc2c2cc(CCc3ccccc3)cnc12
Reaction time: 3 h

Procedure:
To a solution of (E)-2-styrylbenzo[f][1,7]naphthyridin-5-amine (Example 32) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacua and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-phenethylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 1H), 8.32 (d, 1H), 8.10 (dd, 1H), 7.63 (dd, 1H), 7.51 (m, 1H), 7.03-7.32 (m, 6H), 6.16 (bs, 2H), 3.11 (t, 2H), 2.97 (t, 2H). LRMS [M+H]=300.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]#[N:30])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[C:29]([C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:18]3[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:21][NH:22]2)=[CH:27][CH:26]=1)#[N:30]
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cc(C#N)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(C#N)ccc45)C(=O)NC3=O)c21
Temperature: 70 °C

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.410 g, 2.18 mmol) and (6-cyano-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.480 g, 2.10 mmol) in DMF (30 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (7.6 mL, 7.6 mmol) dropwise over 5 minutes. The mixture was heated at 70° C. for 17 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto flash SiO2. Flash chromatography (60–70% EtOAc/hex) gave the title compound as a bright orange-red solid which was dried under vacuum at 75° C. overnight (0.416 g, 54%). 1H NMR (400 MHz, DMSO-d6) 12.29 (br s, 1H), 11.26 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.86 (br s, 1H), 7.63 (d, J=8 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 6.99 (dd, J=8, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 6.60 (d, J=8 Hz, 1H), 6.49 (d, J=3 Hz, 1H), 3.66 (s, 3H). IR (KBR, cm−1) 3282, 2223, 1751, 1698. MS (electrospray, m/z) 367.1 (M++1), 365.2 (M−−1). HRMS 367.1190 (M++1, calcd for C22H15N4O2 367.1195).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[C:20]1[CH:21]=[CH:22]C2N=C(N)N=C(N3C=NC=N3)C=2N=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([CH2:20][CH2:21][CH3:22])[C:3]=3[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Product: CCCc1ncnc2ccc(-c3ccc(F)cc3)nc12

Procedure:
The procedure of example 2 was repeated, except for the use of 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (the synthesis of which has been disclosed in WO2006/135993) instead of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-yl-amine as a starting material. The resulting compound was characterised by its mass spectrum as follows: MS (m/z) 268.0 [M+H]+; HPLC Rt=5.13 minutes (Method A).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]2[N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:25]=[C:24]([CH3:33])[C:23]=2[C:34](OCC)=[O:35])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]2[N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:25]=[C:24]([CH3:33])[C:23]=2[CH2:34][OH:35])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: CCOC(=O)c1c(C)nn(C2CCCCO2)c1-c1cc(OCCOC)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1cc(-c2c(CO)c(C)nn2C2CCCCO2)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a stirred mixture of LiAlH4 (136 mg, 3.58 mmol, 3.99 equiv) in anhydrous tetrahydrofuran (20 mL) maintained under nitrogen at −40° C. was added dropwise a solution of (R/S) ethyl 5-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (410 mg, 0.90 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). The reaction mixture was stirred at −40° C. for 1 h and then quenched with saturated NH4Cl solution (0.2 mL). The solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified on a silica gel column eluted with 30-100% of ethyl acetate in petroleum ether to give 320 mg (86%) of (R/S) (5-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol as a colorless oil. LCMS (method D, ESI): RT=1.51 min, m/z=415.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCC(O)CC2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1cnc(N2CCC(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(5-methyl-pyrazin-2-yl)-piperidin-4-ol (500 mg) and Dess-Martin periodinane (1.30 g) in dichloromethane (20 mL) is stirred at room temperature for 4 h. Aqueous Na2S2O3 solution and NaHCO3 solution are added and the organic phase is separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is triturated with a small amount of methanol. The mixture is filtered and the filtrate is concentrated in vacuo to give the title compound. LC (method 1): tR=0.56 min; Mass spectrum (ESI+): m/z=192 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([OH:37])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].Cl[Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43]>ClCCl.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([O:37][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([CH3:34])([O:35][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: CC[Si](Cl)(CC)CC
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C)O[Si](CC)(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C)O[Si](CC)(CC)CC
Reaction time: 18 h

Procedure:
To a solution of (8E,12E,14E)-7-acetoxy-6,3,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (100 mg, 0.18 mmol) in dichloromethane (6 mL) were added N,N-dimethylaminopyridine (221 mg, 1.8 mmol) and chlorotriethylsilane (272 mg, 1.8 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=20:80) to give the title compound (159 mg, 98%) as a colorless oil.