Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[OH2:24].OO>C(O)=O>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:24])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: O
Agent: OO
Solvent: O=CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
Thebaine (15.94 g) was added to a 250 ml flask. Water (18 ml) was added and the mixture was stirred at room temperature. Formic acid (42 ml) was added over 3 minutes and then the mixture was cooled in an ice bath. Hydrogen peroxide (30%, 6.7 g) was added and the mixture was stirred for 1 hour. The mixture was removed from the ice bath, allowed to warm to room temperature and then heated to 48° C. for 2 hours. The mixture was transferred to a hydrogenation bottle. A 5 wt % palladium on carbon catalyst (2 g) was added and hydrogen was passed through the mixture at approximately 20 psi for 15 hours. The catalyst was removed by passing the mixture through a pad of celite and rinsing the filtered solid with water/formic acid (3:1, 8 ml). The mixture was cooled in an ice bath and 25% sodium hydroxide (109 ml) was added dropwise over 50 minutes to increase the pH to 9–10. The mixture was stirred for 1 hour and 15 minutes and the solid product was filtered, rinsed with cold water and dried under vacuum pump for 3 hours. The product was oxycodone base (14.152 g, 87.7% yield) and contained 178 ppm of the α,β-unsaturated ketone impurity, 14-hydroxycodeinone.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH2:11])=[CH:6][CH:5]=1.CC(S(N)=O)(C)C>>[ClH:1].[F:22][C:3]([F:2])([F:23])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:12]2[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH2:11])=[CH:8][CH:9]=1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Agent: CC(C)(C)S(N)=O
Agent: Cl
Product: NC(c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F

Procedure:
Following the procedure detailed above for Intermediate 2, but replacing (S)-2-methylpropane-2-sulfinamide with racemic 2-methylpropane-2-sulfinamide in STEP 2 gave the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][NH:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7](N)=[O:8].Cl.[OH2:31]>>[CH3:1][CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][NH:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:31])=[O:8]
Reactant: CCCCCCCCCCCCC(C)CNc1cc(C)c([N+](=O)[O-])cc1C(N)=O
Reactant: O
Agent: Cl
Product: CCCCCCCCCCCCC(C)CNc1cc(C)c([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 21.9 grams 2-methyltetradecylamino-4-methyl-5-nitrobenzamide, 60.0 ml water, and 90.0 ml concentrated HCl was heated with stirring at reflux temperature for 16 hours, and then cooled, filtered, washed with water and vacuum dried. The crude product was digested with hot petroleum ether (b.p. = 70-100°), which was cooled and filtered, and the filter cake dried in air overnight. The product was recrystallized from a 3:1 ethanol-water mixture and then recrystallized again from petroleum ether (b.p. 90-100°). Yield = 13.3 grams. m.p. = 98-100°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cccc(Cl)c1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(Cl)c1F
Yield: 88.2 %

Procedure:
Prepared according to Method A step A from 3-chloro-2-fluorobenzoic acid (3.0 g, 17.2 mmol), N,O-dimethylhydroxylamine hydrochloride (2.34 g, 24 mmol), oxalyl chloride (1.5 mL, 17.2 mmol) and 5 mL of pyridine to give the title compound (3.3 g) as an oil. Used as is in the next prep
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:24]([CH2:26][C:27](O)=[O:28])#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([C:27](=[O:28])[CH2:26][C:24]#[N:25])[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)CC#N)CC4C3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (401.6 mg, 1.20 mmol), 2-cyanoacetic acid (110.3 mg, 1.30 mmol) in a mixture of DCM and DMF (4/1 (v/v)), 50 mL) were added HATU (555.6 mg, 1.46 mmol) and Et3N (375.6 mg, 3.71 mmol). The reaction mixture was stirred at rt overnight, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a beige solid (350 mg, 72.8%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[N:9]([CH3:27])[C:10](=[O:26])[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]([NH:16][CH3:17])=[O:15])[N:13]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36](Cl)(=[O:38])=[O:37])=[CH:31][CH:30]=1.[OH-].[Na+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH3:17][NH:16][C:14]([C:12]1[NH:13][C:8]([NH2:7])([S:36]([CH2:35][C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)(=[O:38])=[O:37])[N:9]([CH3:27])[C:10](=[O:26])[C:11]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]
Reactant: Cc1ccc(CS(=O)(=O)Cl)cc1
Reactant: CNC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)C1=C(OCc2ccccc2)C(=O)N(C)C(N)(S(=O)(=O)Cc2ccc(C)cc2)N1
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
Potassium tert-butoxide (93.8 mg, 836 μmol) was added to a solution of 2-amino-5-(benzyloxy)-N,1-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (110 mg, 380 μmol) in THF (10 ml) in DMF (2 ml) [Comment: please check]. After 10 min., the reaction mixture was cooled by an ice bath and then a solution of (4-methylphenyl)methanesulfonyl chloride (93.7 mg, 458 μmol) in THF (2 ml) was added. After 70 min., EtOAc and 1 N NaOH aqueous solution were added. The organic phase was extracted with EtOAc and then with DCM. The combined organic phases were washed with water, and brine, dried over Na2SO4 and evaporated to dryness. Chromatography (silica gel, 0 to 2% MeOH in DCM) provided the title compound as a pale yellow solid (0.080 g; 46%). LCMS: m/z=457 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C:13]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[N:25]1[CH:30]=[C:29]([CH:31]=O)[CH:28]=[N:27][CH:26]=1.Cl>C(O)C>[CH3:9][N:8]1[C:31]([C:29]2[CH:30]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][C:13]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:14][CH2:15]1
Reactant: O=Cc1cncnc1
Reactant: CNc1ncnc(N2CCC3(CC2)C(=O)Nc2ccccc23)c1N
Agent: Cl
Solvent: CCO
Product: Cn1c(-c2cncnc2)nc2c(N3CCC4(CC3)C(=O)Nc3ccccc34)ncnc21
Temperature: 80 °C
Yield: 28.3 %

Procedure:
To a solution of 1′-[5-amino-6-(methylamino)pyrimidin-4-yl]spiro[indole-3,4′-piperidin]-2(1H)-one (100 mg, 0.30 mmol) in anhydrous ethanol (12 mL) were added pyrimidine-5-carbaldehyde (38 mg, 0.35 mmol, Apollo Scientific Ltd.) and catalytic amount of hydrochloric acid (0.05 mL, 4N, Dioxane, Aldrich). The reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 35.0 mg (28% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.P(Br)(Br)[Br:28]>N1C=CC=CC=1>[Br:28][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CO)c1
Reactant: BrP(Br)Br
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1cccc(CBr)c1

Procedure:
The title compound is prepared by the procedure of Example 20 using 2.5 g of product from Example 24, 10 ml acetonitrile, 0.339 g of pyridine and 2.11 g of phosphorus tribromide. The product, 2.27 g, is obtained as colorless needles.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:21]=1)[CH2:10][C:9]2([CH3:29])[CH3:28])=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:28][C:9]1([CH3:29])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:21]=2)[CH2:10]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CC(c2cncc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
A mixture of 4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.40 g, 1.0 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.30 g, 81%) as a white solid which was used for next step without further purification: MS (ESI) M+1=368.2;
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N12CCC(CC1)C(O)C2>CCOCC>[OH:21][CH:20]([C:2](=[CH2:3])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CCCCCc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: OC1CN2CCC1CC2
Solvent: CCOCC
Product: C=C(C(=O)OC(C)(C)C)C(O)CCCCc1ccccc1
Reaction time: 384 h
Yield: 89.8 %

Procedure:
t-Butyl acrylate (6.7 g, 46 mmol), 5-phenyl pentanal (3.7 g, 23 mmol) and 3-quinuclidinol (0.38 g, 3 mmol) are combined and stirred under N2. After 24 hours stirring is halted and the resulting solution is allowed to sit at ambient temperature for 16 days. TLC analysis (30% ether in petroleum ether) showed that the reaction is nearly complete. The product is purified by column chromatography (silica, 20% ether in petroleum ether) to yield t-butyl 2-(1-hydroxy-5-phenylpentyl)acrylate (6 g, 45%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.18-7.14 (m, 3H), 6.10 (d, J=1.1 Hz, 1H), 5.67 (s, 1H), 4.33 (q, J=6.7 Hz, 1H), 2.74 (d, J=6.7 Hz, 1H), 2.61 (t, J=7.6 Hz, 2H), 1.70-1.53 (m, 4H), 1.50 (s, 9H), 1.50-1.32 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 165.93, 143.91, 142.51, 128.32, 128.20, 125.57, 123.82, 81.35, 71.79, 36.17, 35.82, 31.26, 28.04, 25.54; MS (EI) m/e 291 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:44][CH:45]1[O:49][CH2:48][CH2:47][O:46]1.CS(C)=O>C1COCC1.O>[O:46]1[CH2:47][CH2:48][O:49][CH:45]1[CH2:44][N:18]1[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:30])[F:31])[CH:23]=2)[N:21]=[C:17]1[CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: BrCC1OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2OCCO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
The solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1100.00 mg; 2.46 mmol; 1.00 eq.) in 2.0 ml of THF was cooled to −20° C., NaHMDS (541.00 mg; 2.95 mmol; 1.20 eq.) was added dropwise and the resulting mixture was stirred at RT for 30 mins. 2-Bromomethyl-[1,3]dioxolane (0.76 ml; 7.38 mmol; 3.00 eq.) was added and stirred at RT for 5 min. DMSO (10 ml) was added and the mixture was placed in microwave at 100° C. for 2 hr. The reaction mixture was cooled and diluted with water and extracted with EA. The organic layer was washed with brine, separated, dried and concentrated. The residue was subjected to snap column (100 g), eluted with 20%-80% EA in hexane to give the title compound (1000 mg, yield 76.2%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([Cl:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O[CH2:13][C:14]1[O:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([CH:13]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:11])[N:2]([CH3:1])[CH:3]=1)[C:14]1[O:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1)=[CH:3][N:2]2[CH3:1]
Reactant: O=Cc1ccc(CO)o1
Reactant: Cn1ccc2c(Cl)cccc21
Product: Cn1cc(C(c2ccc(CO)o2)c2cn(C)c3cccc(Cl)c23)c2c(Cl)cccc21

Procedure:
The compound Bis(4-chloro-1-methylindol-3-yl)-(5-hydroxymethyl-2-furyl)methane was prepared following procedure A, starting from N-methyl 4-chloro indole and 5-hydroxy methyl furfural. LC: Tr 2.73 min, MS: 439 (M+H)+
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:14][OH:15])([CH3:13])([CH3:12])[CH3:11]>Cl.C(Cl)(Cl)Cl>[C:10]([N+:14]([O-:15])=[CH:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)NO
Reactant: O=CCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[N+]([O-])=CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a mixture of phenyl-acetaldehyde (1.20 g, 10.00 mmol) and chloroform (50 ml) was added N-tert-butylhydroxylamine (1.07 g, 12.00 mmol) followed by 5 drops of conc. HCl. The mixture was stirred at rt for 18 h. The mixture was concentrated under vacuum to give an oil. The residue was purified by column chromatography (hexane:EtOAc=1:1) followed by EtOAc to give the title compound as a white solid: Yield: 80%, m.p. 143° C.: 1H NMR (CDCl3) δ 7.38 (m, 5H), 6.90 (s, 1H), 4.95 (dd, 2H), 1.25 (s, 9H).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1.O>CCCCCC.O1CCCC1>[Cl:7][CH:8]=[C:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1
Reactant: COC(=O)c1ccc2c(c1)CCC(=O)CO2
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(c1)CCC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
0.08 ml (0.2 mmol) of a 1.9M solution of n-butyllithium in hexane is added dropwise to a suspension of 76 mg (0.22 mmol) of chloromethyltriphenylphosphonium chloride in 1.7 ml of tetrahydrofuran cooled to 0° C. The solution is stirred for one hour and then 40 mg (0.18 mmol) of methyl 3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 4, in 2.5 ml of tetrahydrofuran are added at 0° C. via a hollow tube. The solution is stirred at ambient temperature for 1 h 30 and then water is added. After concentrating the solution, dichloromethane is added. The phases are separated and then the aqueous phase is extracted with dichloromethane. The combined organic phases are then washed using brine, are then dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to provide 11 mg (24%) of methyl 3-(chloromethylene)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of a mixture of two isomers in a Z/E ratio (70/30); 1H NMR (300 MHz, CDCl3): 2.6 (m, 2H), 2.99 (m, 2H), 3.9 (s, 3H), 4.79 (s, 2H), 6.07 (s, 1H), 7.04 (d, J=8.3 Hz, 1H), 7.84 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:26]([O:25][C:21]1[CH:20]=[C:19]([C:11]2[C:12]3[C:17]([NH2:18])=[N:16][CH:15]=[N:14][C:13]=3[N:9]([C@H:7]3[CH2:8][C@@H:5]([CH2:3][N:2]([CH3:33])[CH3:1])[CH2:6]3)[CH:10]=2)[CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)C(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C

Procedure:
A solution of 42 mg (0.095 mmol) of cis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid dimethylamide in 2 ml of anhydrous THF is added dropwise at 0° C. to a 10 mg of lithium aluminium hydride suspended in 2 ml of anhydrous THF. The reaction mixture is slowly warmed to RT overnight. For working-up, the reaction mixture is cooled to 0° C. and then water and a 15% NaOH solution are added in succession thereto. The solution is partitioned between water and ethyl acetate. Drying the organic layer over magnesium sulfate, concentrating in vacuo and purifying by medium-pressure liquid chromatography yield cis-5-(3-benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=5.98 min (Grad 2); ES-MS: m/eo=428.1.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:57])[CH2:17][CH2:18][C:19](=[O:56])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:27](=[O:47])[CH2:28][CH2:29][C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:58](OC(=O)C)(=[O:60])[CH3:59]>N1C=CC=CC=1>[CH2:1]([O:8][N:9]([C:16](=[O:57])[CH2:17][CH2:18][C:19](=[O:56])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:27](=[O:47])[CH2:28][CH2:29][C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:58](=[O:60])[CH3:59])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Reaction time: 12 h
Yield: 91 %

Procedure:
6,17,28-Tris (benzyloxy)-7,10,18,21,29-pentaoxo-6,11,17,22,28-pentaazatriacontanenitrile (13 ) was prepared by dissolving compound (12) (1.1 g, 1.4 mmol) in pyridine (16 ) mL), adding acetic anhydride (4 mL) and stirring the solution for 12 hours. After removal of solvents under high vacuum, water was added, followed by extraction with CHCl3. The organic extracts were washed with 1 N HCl and saturated NaHCO3. Column chromatography (5% CH3OH/CHCl3) gave 1.05 g (91%) of (13): NMR δ 1.4-1.59 (m, 4 H), 1.59-1.70 (m, 6 H), 1.70-1.85 (m, 6 H), 2.1 (s, 3 H), 2.35 (t, 2 H), 2.40-2.55 (m, 4 H), 2.75-2.90 (m, 4 H), 3.18-3.28 (m, 4 H), 3.6-3.7 (m, 6 H), 4.8 (s, 2 H), 4.82 (s, 2 H), 4.84 (s, 2 H), 6.20-6.75 (m, 2 H), 7.4 (s, 15 H) . Anal. calcd. for C46H62N6O8 : C, 66.30; H, 7.68. Found: C, 66.44; H, 7.66 [Bergeron et al, J. Org. Chem., supra].
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(Oc3ccccc3)cccc12
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc2c(Oc3ccccc3)cccc12
Temperature: 97.5 °C
Yield: 60.1 %

Procedure:
Into 50 mL of glacial acetic acid, 3.7 g of 1-methoxy-5-phenoxynaphthalene prepared as above, followed by 20 mL of 40% aqueous hydrogen bromide was stirred. The mixture was heated at 95-100° C. for 16 hours. The solvent was removed under vacuum, and the residue was redissolved in ethyl acetate and washed three times with brine. The organic layer was dried over magnesium sulfate and filtered. After removing solvent, the residue was chromatographed over silica gel with a gradient elution of 0 to 30% ethyl acetate in hexane, providing 2.10 g (59%) of 1-hydroxy-5-phenoxynaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)=[C:47]([C:58]([F:61])([F:60])[F:59])[CH:46]=1>CN(C=O)C.CO>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:57][C:54]1[CH:55]=[CH:56][N:52]([CH2:51][C:48]2[CH:49]=[CH:50][C:45]([I:44])=[CH:46][C:47]=2[C:58]([F:61])([F:59])[F:60])[N:53]=1)=[O:10]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1ccncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-fluoro-4-pyridinecarboxylic acid (38 mg, 0.269 mmol, Aldrich) was added a solution of HATU (100 mg, 0.263 mmol, Advanced asymmetrics) in DMF (0.5 ml), DIPEA (0.11 ml, 0.630 mmol) and then a solution of 1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 39)(75 mg, 0.204 mmol) in DMF (0.5 ml). The resulting orange solution was stirred at ambient temperature overnight. The reaction mixture was diluted with methanol (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (86 mg); LCMS: (System 4) MH+=491, tRET=3.0 min.