Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][C:12]([F:15])([F:14])[CH3:13])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:19]([O:18][C:16]([N:6]1[CH2:7][CH:8]([CH2:10][CH2:11][C:12]([F:14])([F:15])[CH3:13])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)C1CC(CCC(C)(F)F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(F)(F)CCC1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a mixture of 4-(3,3-difluoro-butyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (92.7 mg, 0.23 mmol, 1 equiv) in THF (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (49 mg, 1.17 mmol, 5 equiv). The reaction mixture was stirred at rt overnight. the THF was removed under vacuum. The residue was diluted with water, washed with ether. The aqueous layer was taken up in ethyl acetate, partitioned with 10% citric acid. The organic layer was washed with water (1×), brine (1×), dried and concentrated to give a white solid, 4-(3,3-difluoro-butyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (59.7 mg, 83%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:24]4[CH2:27][CH:26]([N:28]5[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]5)[CH2:25]4)[N:14]3C3CCCCO3)=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:9]=2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]=2[N:4]=1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:24]4[CH2:25][CH:26]([N:28]5[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]5)[CH2:27]4)[NH:14]3)=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:9]=2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)n(C3CCCCO3)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)[nH]c2n1
Reaction time: 24 h

Procedure:
To a solution of 4-{1-[2-(2-ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purin-8-ylmethyl]azetidin-3-yl}piperazin-2-one (470 mg, 0.78 mmol) in dioxane (20 mL) was added 4M HCl in dioxane (1 mL). The resulting suspension was stirred at r.t for 24 h then the precipitate collected by filtration, washing with dioxane. The resulting solid was partitioned between EtOAc and H2O and the aqueous layer basified to pH 11 with NH4OH. The aqueous phase was neutralised to pH 7 with HCl then loaded onto an Isolute® SCX-2 cartridge which was washed with H2O and MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (C18, MeOH:H2O, 30-95%) then loaded onto an Isolute® SCX-2 cartridge which was washed with H2O and MeOH and the product eluted with 2M NH3/MeOH affording 812 (69 mg, 17%). LCMS (method I): RT 2.16 min, [M+H]+ 517.3. 1H NMR (DMSO, 400 MHz): δ 7.95-7.94 (1 H, m), 7.73 (1 H, s), 7.63-7.62 (1 H, m), 7.25-7.22 (2 H, m), 4.24 (4 H, brd s), 3.79-3.74 (6 H, m), 3.46 (2 H, s), 3.23 (3 H, q, J=7.46 Hz), 3.16-3.04 (5 H, m), 2.84 (2 H, s), 2.45-2.44 (2 H, m), 1.31 (3 H, t, J=7.45 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11](CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[NH:11][CH2:10][C@H:9]1[CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H]1CN[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 86 %

Procedure:
(2R,5S)-4-Benzyl-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (5.9 g, 15.25 mmol) and 10% Pd/C (2.13 g, 1.5 mmol) were dissolved in glacial acetic acid/ethanol (27.2 mL/72.6 mL) and stirred under hydrogen at 1 bar for 1 h. The mixture was filtered and the filtrate concentrated. Saturated aqueous sodium hydrogen carbonate and EtOAc were added. The EtOAc layer was separated and the aqueous phase extracted with DCM (3×). The combined DCM layers were dried with sodium sulfate, filtered and concentrated. The residue was azeotroped with toluene, to give the title compound (3.9 g), 1H NMR (CDCl3): 4.23-4.08 (1H, m), 3.95-3.77 (1H, m), 3.69 (1H, d), 3.59-3.46 (1H, m), 3.46-3.34 (1H, m), 3.34-3.07 (3H, m), 3.07-2.89 (1H, m), 2.55-2.39 (3H, m), 2.15-1.92 (2H, m), 1.48 (9H, s), 1.23 (3H, d).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([OH:22])=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:15]([CH:16]=[O:17])[C:14]=1[O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1cc(Cl)cc(OCCCOCc2ccccc2)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cc(Cl)cc(OCCCOCc2ccccc2)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
To a solution of 3-(3-benzyloxy-propoxy)-5-chloro-2-hydroxy-benzaldehyde (5.3 g, 16.6 mmol) and pyridine (3.4 mL, 41.5 mmol) in CH2Cl2 (70 mL) at 0° C. was added Tf2O (3.1 mL, 18.3 mmol) drop-wise over 5 minutes period and the reaction mixture was stirred for 3 h at room temperature. The solution was diluted with CH2Cl2 (100 mL), washed with water, brine, dried over Na2SO4, then concentrated under reduced pressure. The product was purified by silica gel column chromatography (2:1 hexanes-EtOAc mobile phase) generating the title compound (3.8 g, 8.5 mmol, 51%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.18 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.37-7.29 (m, 6H), 4.52 (s, 2H), 4.23 (t, J=6.2 Hz, 2H), 3.69 (t, J=5.8 Hz, 2H), 2.16 (t, J=6.0 Hz, 2H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −73.23 (s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>>[CH3:15][O:16][CH:17]([O:21][CH3:22])[N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:10][CH2:11]1
Reactant: COC(OC)N(C)C
Reactant: c1cn(CCCC2CCNCC2)cn1
Product: COC(OC)N1CCC(CCCn2ccnc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[3-(1H-imidazol-1-yl)propyl]-piperidine (1.5 g, 0.0078 M) and dimethylformamide dimethylacetal (10 ml) was heated at 100° C. for 16 hrs. The excess of dimethylformamide dimethylacetal was removed to give 4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0053 M) and diisopropylethylamine (1.03 ml) in dry CHCl3 (9 ml) was added the above piperidinecarboxaldehyde in CHCl3 (5 ml) at 0° C. and stirred at that temperature for 1 hr, then at room temperature for 3 hrs. After the reaction, the solvent was removed and the residue dissolved in water (40 ml). The aqueous solution, washed with diethyl ether, was adjusted to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[3 -(1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 mole hydrochloride monohydrate (0.87 g, 39% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH:11]([N:24]1[CH2:27][C:26]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-Methoxyphenylmagnesium bromide (5.9 ml, 1M solution in tetrahydrofuran, 5.9 mmol) was added to a cooled (−78° C.) solution of 1-benzhydryl-azetidin-3-one (WO 9412181) (1 g, 4.2 mmol) in tetrahydrofuran (20 ml), and the reaction stirred at −78° C. for 15 minutes, then allowed to warm to room temperature over 30 minutes. The mixture was partitioned between water (100 ml) and ethyl acetate (100 ml), the layers separated, and the aqueus phase extracted with ethyl acetate (100 ml). The combined organic solutions were washed with brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using pentane:ethyl acetate (50:50) as eluant to afford the title compound as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[NH:14][C:13]1=[O:25].[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:7]([N+:26]([O-:28])=[O:27])=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[NH:14][C:13]1=[O:25]
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(C(F)(F)F)ccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(C(F)(F)F)cc([N+](=O)[O-])c1O
Temperature: 0 °C

Procedure:
To an ice cooled solution of 1-(2-Hydroxy-5-trifluoromethylphenyl)-5-trifluoromethyl-1,3-dihydro-2H-benzimidazol-2-one (1.38 mmol, 0.50 g) in concentrated sulphuric acid (6 ml) is added an ice cooled solution of potassium nitrate (1.38 mmol, 0.14 g) in concentrated sulphuric acid (8 ml). The reaction mixture is allowed to reach room temperature and is poured into ice. The crude product is collected by filtration and subjected to column chromatography using methylenechloride+methanol (9+1 ) as eluent. The fractions containing the product are concentrated in vacuo yielding the title compound as slightly yellow crystals, M.p.>360° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[S:4][C:3]=1[CH:9]=[O:10].[BH4-].[Na+]>C(O)C>[OH:10][CH2:9][C:3]1[S:4][C:5]([CH3:8])=[C:6]([CH3:7])[C:2]=1[CH3:1]
Reactant: Cc1sc(C=O)c(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(CO)c(C)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.9 G. of 3,4,5-trimethyl-2-thiophenecarboxaldehyde were dissolved in 20 ml. of ethanol. The resulting solution was cooled to 0°-5° C. and 125 mg. of sodium borohydride were added in small portions. The resulting reaction mixture was stirred at room temperature for 3 hours, poured into ice water, extracted with ethyl acetate, dried with sodium sulfate, filtered and evaporated. The resulting crystalline 2-hydroxymethyl-3,4,5-trimethyl-thiophene had m.p. 45°-48° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[CH2:17][CH2:16][N:15]([C@@:18]3([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:5]=2[N:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:8]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[C:4]2[CH2:17][CH2:16][N:15]([C@@:18]3([CH3:30])[CH2:22][CH2:21][NH:20][CH2:19]3)[C:5]=2[N:6]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(N2CCc3c(Cl)nc(N4CCOCC4)nc32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@]1(N2CCc3c(Cl)nc(N4CCOCC4)nc32)CCNC1
Reaction time: 20 h
Yield: 305.3 %

Procedure:
A solution of 4 M hydrochloric acid in dioxane (5 mL) was added to a solution of the product of Example 4, step 2, tert-butyl(3S)-3-[4-chloro-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (424 mg, 1.00 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 20 h. The reaction mixture was concentrated to give 4-chloro-7-[(3S)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine hydrochloride (550 mg). This material was dissolved in a biphasic mixture of DCM (10 mL) and saturated aqueous
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:15][C:14]=1[C:31](=[O:33])[CH3:32])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:34](OCC)(=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>C(O)C.O>[CH2:38]([O:37][C:35](=[O:36])[C:34]([OH:40])=[CH:32][C:31]([C:14]1[CH:15]=[C:16]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:18][C:13]=1[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:33])[CH3:39]
Reactant: CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(O)=CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 93.1 %

Procedure:
Sodium ethoxide (2.8 g, 41 mmol) was added to a suspension of the 1-(2,4-bis-benzyloxy-5-tert-butyl-phenyl)-ethanone (7.8 g, 20 mmol) in ethanol (40 ml). Diethyl oxalate (4 ml, 29.5 mmol) was added and the resulting suspension heated under reflux for ˜2 hrs. to give a pale red solution. The solution was allowed to cool and poured into water (200 ml), the mixture was acidified with hydrochloric acid (50 ml, 1M) and extracted with dichloromethane (150 ml). The extracts were washed with water (2×200 ml) and saturated aqueous sodium chloride solution (100 ml). The solution was dried over anhydrous sodium sulphate and concentrated to a yellow gum. Trituration with hexane gave a yellow solid. Solids were removed by filtration and washed with hexane and dried in vacuo (40° C.), to give 4-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as a yellow powder (9.1 g, 93%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].[C:25]([O:28][C:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])[CH3:26]>C(#N)C>[CH2:1]([N:3]([CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:28][C:25](=[O:27])[CH3:26])([CH3:35])[CH3:36])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CC(=O)OC(C)(C)CCCCBr
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 5-acetoxy-1-bromo-5-methylhexane (Step V) to give the titled product, a compound of Formula I'. The mass spectrum had M+ at m/z 442.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[N:6][CH:7]=1.[CH3:13][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:12])([CH3:13])[CH:9]([F:10])[F:11])=[N:6][CH:7]=1
Reactant: C[Mg+]
Reactant: O=C(c1ccc(Br)cn1)C(F)F
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cn1)C(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-2,2-difluoroethanone (1.5 g, 6.4 mmol) in THF (15 mL) under nitrogen was added MeMgBr (3.2 mL, 9.6 mmol, 3.0 M in THF) dropwise at −15° C. The resulting solution was stirred at ambient temperature for 2 hours before the addition of saturated aqueous NH4Cl (10 mL) at 0° C. The resulting mixture was vigorously stirred for 10 minutes, and then extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 1-3% EtOAc/hexane) to afford the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=2.0 Hz, 1H), 7.92 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 5.76 (t, J=56.4 Hz, 1H), 5.22 (br, 1H), 1.60 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CN=C1.O>C(#N)C>[Cl:3][C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(O)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Reactant: O=S(Cl)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Cl)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Temperature: 0 °C
Yield: 70.6 %

Procedure:
Thionyl chloride (0.57 g) was added dropwise to a solution of ethyl (RS)-2-hydroxy-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.2 g) and imidazole (0.32 g) in dry acetonitile (7 cm3), whilst the reaction temperature was maintained at 0° C. The mixture was allowed to warm to the ambient temperature and stirred for a period of sixteen hours, after which time it was poured into water, and extracted into dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, passed through a short plug of silica, and concentrated by evaporation of the solvent under reduced pressure to give ethyl (RS)-2-chloro-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate as a yellow oil (0.15 g).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[CH:21][N:22]([CH3:34])[C:23]=2[C:24]2[S:33][C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH2:32])[C:26]=3[CH:25]=2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C1COCC1>[NH2:32][C:31]1[C:26]2[CH:25]=[C:24]([C:23]3[N:22]([CH3:34])[CH:21]=[N:20][C:19]=3[C:15]3[CH:14]=[C:13]([NH:12][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:18]=[CH:17][CH:16]=3)[S:33][C:27]=2[N:28]=[CH:29][N:30]=1
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1cnc(-c2cccc(NC(=O)OCc3ccccc3)c2)c1-c1cc2c(N)ncnc2s1
Reaction time: 1 h
Yield: 28 %

Procedure:
Benzylchloroformate (0.027 mL) was added to a solution of 6-[4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 110) (40 mg) and pyridine (0.02 mL) in THF (7 mL). The mixture was stirred under an inert atmosphere for 1 hour, then quenched with H2O (10 mL) and extracted EtOAc (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with CH2Cl2:MeOH (0-10%) gave the title compound as a gum (16 mg, 28%);
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:39])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of acryloyl chloride (13 mg, 0.14 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 160, 100 mg, 0.13 mmol) in THF (3 mL), which was cooled in an ice/CH3OH bath to approximately −15° C. The mixture was stirred for 1 h and allowed to warm to −0° C. The mixture was then diluted with CH2Cl2 (50 mL) and the resulting solution was washed with sat. NaHCO3 (50 mL). The aqueous solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo onto silica. Patrial purification by FCC, eluting with 0-3.5% 7N methanolic ammonia in CH2Cl2 provided some of the title compound. Further purification by FCC, eluting with 0-1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (33 mg, 49%) as a yellow solid; 1H NMR: 1.77 (1H, s), 1.94-2.15 (1H, m), 2.10 (3H, s), 2.29 (1H, d), 2.39-2.48 (1H, m), 2.87 (1H, s), 3.11-3.20 (1H, m), 3.33-3.42 (2H, m), 3.81 (3H, s), 4.26-4.34 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.53 (1H, dd), 6.67 (1H, s), 7.04 (1H, td), 7.21 (1H, d), 7.36-7.43 (1H, m), 8.03 (1H, s), 8.08 (1H, s), 8.30 (1H, d), 8.42 (1H, d), 8.73-8.79 (2H, m), 9.41 (1H, s); m/z: ES+ MH+ 511.16.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH:8]=[N:9]O)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[NH2:9][CH2:8][C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]=1[OH:14]
Reactant: CC(C)(C)c1cccc(C=NO)c1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(CN)c1O
Yield: 23.7 %

Procedure:
3-tert-butyl-2-hydroxybenzaldehyde oxime (550 mg, 2.9 mmol) in EtOAc (10 mL) and MeOH (10 mL) was hydrogenated at balloon pressure in the presence of 10% Pd on carbon (100 mg) for 15 h. The reaction mixture was filtered over celite and concentrated. The residue was dissolved in EtOAc and 0.5 N HCl (10 mL). The layers were separated and the aqueous layer was treated with 1N NaOH solution until pH=9. The resulting aqueous layer was extracted with CHCl3 (3×10 mL). The combined CHCl3 was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide to desired product (123 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1>>[NH:29]1[C:26]2=[N:27][CH:28]=[C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:24]=[C:25]2[CH:31]=[CH:30]1
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 78.7 %

Procedure:
The process is performed according to a method similar to that described in Example 1.3 starting with 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.22 g (1.67 mmol) of 5-amino-1H-pyrrolo[2,3-b]pyridine (Synthesis 2005, 15, 2503). 0.44 g of the expected product is thus isolated in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:15][NH2:16].CO>>[CH3:15][NH:16][C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1cccnc1Cl
Reactant: CN
Solvent: CO
Product: CNc1ncccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h
Yield: 92 %

Procedure:
t-Butyl 2-chloronicotinate (k) (50.0 g, 0.234 mol) was dissolved in a 40% methylamine-methanol solution (300 mL) and the mixture was stirred at room temperature for 30 h. The mixture was evaporated under reduced pressure and the resulting residue was dissolved in EtOAc (750 mL). The EtOAc solution was washed with water, dried over MgSO4 and evaporated under reduced pressure. The obtaining oily crude product was purified by a short silica gel column chromatography (ca. 300 g of silica gel, eluent: EtOAc/hexane=1/3) to give t-butyl 2-(N-methylamino)nicotinate (1) (45.0 g, ca. 92%) contaminated by starting meterial; 1H NMR (CDCl3): δ 1.57 (s, 9H), 3.05 (d, J=5.0 Hz, 3H), 6.49 (dd, J=4.6 and 7.6 Hz, 1H), 7.96 (bs, 1H), 8.04 (dd, J=2.0 and 7.6 Hz, 1H), 8.28 (dd, J=2.0 and 4.6 Hz, 1H).