Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:12]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:13]=3[S:14][C:15]=2C(O)=O)[CH2:7][CH2:6]1)=[O:4]>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.[Cu]>[CH3:1][O:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:12]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:13]=3[S:14][CH:15]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)N1CCC(c2c(C(=O)O)sc3cc(C(F)(F)F)ccc23)CC1
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: COC(=O)N1CCC(c2csc3cc(C(F)(F)F)ccc23)CC1
Temperature: 200 °C
Yield: 82.4 %

Procedure:
A mixture of 4-(2-carboxy-6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (4.3 g, 11.1 mmol) and copper (705 mg, 11.1 mmol) in quinoline (28 mL) was heated at 200° C. for 45 minutes. Upon cooling to room temperature the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with 5% HCl (2×20 mL), water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was separated via chromatography (30% EtOAc in heptane) yielding 3.14 g (82%) of the desired product as a white solid.
Reaction SMILES: [CH2:1](Br)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].CS(C)=O.[CH3:29][O:30][C:31]1[CH:38]=[C:37]([O:39][CH3:40])[C:34]([CH:35]=O)=[C:33]([OH:41])[CH:32]=1>>[CH3:40][O:39][C:37]1[C:34]([CH2:35][CH2:1][CH3:2])=[C:33]([OH:41])[CH:32]=[C:31]([O:30][CH3:29])[CH:38]=1
Reactant: CCBr
Reactant: COc1cc(O)c(C=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CCCc1c(O)cc(OC)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Triphenylphosphine ethylbromide (4.1 g) was added to 2N sodium hydroxide/dimethyl sulfoxide solution (11 ml), prior to stirring at 50° C. for 30 minutes. To the mixture was added 4,6-dimethoxy-2-hydroxybenzaldehyde (1 g), for stirring at 50° C. overnight. The resulting solution was partitioned between ethyl acetate and dilute hydrochloric acid, and the resulting ethyl acetate phase was washed in water and subsequently in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=3:1), followed by addition of a catalytic amount of platinum dioxide for hydrogenation, to recover 3,5-dimethoxy-2-propylphenol (0.5 g; yield of 46%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.Br[CH:18]([CH2:26][CH3:27])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:13]([C:7]1[CH:6]=[C:5]([N:4]([CH2:3][C:2]([F:15])([F:16])[F:1])[CH:18]([CH2:26][CH3:27])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:10]=[CH:9][C:8]=1[C:11]#[N:12])#[N:14]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C#N
Product: CCC(C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 1B using 4-[(2,2,2-trifluoroethyl)amino]-1,2-benzenedicarbonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 368 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:35]C(=O)OC(C)(C)C)[CH2:34][O:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:35])[CH2:32][O:33][CH2:34]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a suspension of tert-butyl {3-[4-(2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]oxetan-3-yl}carbamate (29 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0° C. dropwise. After being stirred at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. Purification by column chromatography (NH-silica gel: 0-3% methanol in chloroform) gave the product (16 mg, 68%). 1HNMR (DMSO-d6) 400 MHz δ: 8.57 (s, 1H), 8.08 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.8, 1.4 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.53-7.49 (m, 2H), 7.38-7.21 (m, 7H), 7.12 (t, J=7.6 Hz, 1H), 6.90 (dd, J=8.0, 1.6 Hz), 6.74 (dd, J=8.0, 4.8 Hz, 1H), 4.71-4.65 (m, 4H). LCMS: 458 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([NH:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[H][H]>CO.[Pt]=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13])=[CH:10][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CO
Product: CC(C)OC(=O)Nc1ccc(N)c(N)c1
Yield: 66.3 %

Procedure:
A mixture of a solution of 2-nitro-4-isopropoxycarbonylaminoaniline (17.9 g, 0.075 mole) in methanol (450 ml) and platinum oxide (1.0 g) was shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature for several hours, during which time 5.04 liters of hydrogen were absorbed. The mixture was filtered, and the methanol removed in vacuo and the dark solid residue recrystallised from benzene to give 1,2-diamino-4-isopropoxycarbonylaminobenzene (10.4 g), m.p. 108°-110° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+]>C1COCC1>[F:19][C:16]([F:17])([F:18])[C:14]1[O:13][N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[CH:6][CH:7]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester (Preparative Example 9, 2.25 g, 7.86 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (660 mg, 15.72 mmol) and allowed to stir for 16 hr. The reaction was then evaporated to a small volume and treated with a 1 N aqueous hydrochloric acid solution (25 mL) and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (1.48 g, 73%). 1H NMR (DMSO-d6) 8.06 (s, 4 H), 8.13 (s, 1 H). 13C NMR 106.5, 118.0 (q, J=270), 127.9, 130.8, 131.2, 132.4, ˜150 quartet not resolved from baseline noise, 133.8, 162.8, 167.3. 19F NMR −63.6. LC/MS 6.04 min, [M+1]+ 258.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.CC1C=CC(S(O[CH2:41][C:42]2([C:45]#[N:46])[CH2:44][CH2:43]2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:41][C:42]4([C:45]#[N:46])[CH2:44][CH2:43]4)[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC5(C#N)CC5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 70 °C

Procedure:
To a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.078 mmol) in acetonitrile (1.0 mL) was added (1-cyanocyclopropyl)methyl 4-methylbenzenesulfonate (16 mg, 0.10 mmol, prepared according to the procedure described in patent WO2005063247) followed by DIEA (30 mg, 0.23 mmol) and KI (catalytic amount). The resulting mixture was heated to 70° C. for 14 h and then cooled down to room temperature. The resulting mixture was directly purified by preparative RP-HPLC to provide 1-((4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-piperidin-1-yl)methyl)cyclopropanecarbonitrile; ESMS m/z 491.2 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=2)[N:13]([CH3:21])[N:12]=1>O>[NH2:20][C:16]1[N:15]=[C:14]2[N:13]([CH3:21])[N:12]=[C:11]([C:4]3[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=3[OH:2])[C:19]2=[CH:18][N:17]=1
Reactant: COc1ccc(-c2nn(C)c3nc(N)ncc23)c(OC)c1
Solvent: O
Product: Cn1nc(-c2ccc(O)cc2O)c2cnc(N)nc21

Procedure:
This compound is prepared analogously to Example 91 by replacing 3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine phenyl) (Example 88) with 3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 89). The addition of water during the aqueous quench results in a precipitate but on filtration a gum forms, this gum is therefore triturated with diethyl ether (50 ml) to form a solid, which is collected by filtration and dried under vacuum to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:28])=[C:20]([C:23](OCC)=[O:24])[CH2:21][CH3:22])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:23](=[O:24])[C:20]([CH2:21][CH3:22])=[C:19]([CH3:28])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCc1c(C)[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methyl-1-butenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-ethyl-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 176°-178° C.,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O.NN.O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][NH2:16])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1c2ccccc2C(=O)N1CCn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 2-(2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethyl)-isoindoline-1,3-dione (155 mg, 0.40 mmol) in EtOH (4.0 ml) was added hydrazine hydrate (0.194 ml, 4.0 mmol). The reaction mixture was refluxed for 1 h and left to cool down to RT. Water (20 ml) was added and the mixture was extracted with DCM (3×20 ml). Combined organic phases were dried over Na2SO4 and evaporated to yield quantitative amount of the title compound (102 mg, 100%). Product was used in the next step without analysis.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[C:17]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:15]=[CH:14][N:13]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[C:17]([C:2]2[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: CSc1cc(I)nc(C)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1cc(-c2nccnc2F)nc(C)n1
Temperature: 140 °C
Yield: 11.9 %

Procedure:
A glass microwave reaction vessel was charged with 4-iodo-2-methyl-6-(methylthio)pyrimidine (266 mg, 1.000 mmol), 2-fluoro-3-(tributylstannyl)pyrazine (387 mg, 1.000 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.100 mmol) in toluene (3 mL). The reaction mixture was stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 40 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 4-(3-fluoropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (28 mg, 0.119 mmol, 12% yield). 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H); 8.32 (s, 1H); 7.67 (s, 1H); 2.79 (s, 3H); 2.63 (s, 3H). m/z (ESI, +ve ion) 237.1 (M+H)+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][C:29]1[C:30]([F:57])=[C:31]([CH:54]=[CH:55][CH:56]=1)[CH2:32][N:33]1[CH2:53][CH2:52][C:36]2([O:41][CH2:40][CH2:39][N:38]([C:42]([C:44]3[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=3)=[O:43])[CH2:37]2)[CH2:35][CH2:34]1)(C(C)(C)C)(C)C>C1COCC1>[F:57][C:30]1[C:29]([CH2:28][CH2:27][OH:26])=[CH:56][CH:55]=[CH:54][C:31]=1[CH2:32][N:33]1[CH2:34][CH2:35][C:36]2([O:41][CH2:40][CH2:39][N:38]([C:42]([C:44]3[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=3)=[O:43])[CH2:37]2)[CH2:52][CH2:53]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO[Si](C)(C)C(C)(C)C)c4F)CC3)C2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
TBAF (1M in THF, 13.9 mL) was added to a solution of (9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone [Example 7, step a] (5.35 g) in THF (50 mL) and the resulting mixture was stirred for 1 h. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The crude material was purified by flash silica chromatography, elution gradient 4:1 isohexane:ethyl acetate to 100% ethyl acetate to give the subtitled compound as a clear oil. Yield 3.90 g.
Reaction SMILES: C([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.Cl>C(O)C>[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc2cccc(N3CCNCC3)c2c1
Yield: 47 %

Procedure:
The product of Example 11 (7-benzamido-1-(1-piperazinyl)-naphthalene, (0.063 g, 0.19 mmol) was combined with hydrochloric acid in ethanol (4 mL) and refluxed 16 hours. The reaction was concentrated at reduced pressure and the residue was neutralized with 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was washed with brine, dried and concentrated to a tan solid (0.041 g). The solid was recrystallized from ethyl acetate/hexane to give 0.020 g (47%) of the title compound as light tan crystals. mp 184°-186° C. HRMS m/e calculated for C14H17N3 : 227.1419. Observed m/e 227.1405.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:10]=2)[CH2:25][CH2:24]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2nccs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3nccs3)no2)CC1
Yield: 92.1 %

Procedure:
About 2 min after dissolving 3-(3-(1,3-thiazol-2yl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol)and 1-(2-methoxyphenyl)piperazine (9.2 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 15.5 hr and followed the same processes as in Example 1 to obtain 17.7 mg (95.9%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[Cu][C:31]#[N:32]>N1C=CC=CC=1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([C:31]#[N:32])[N:15]=2)=[N:6]1
Reactant: N#C[Cu]
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: c1ccncc1
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(C#N)c21
Yield: 19.4 %

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 in pyridine (3 ml) were admixed with 37 mg (0.419 mmol) of copper(I) cyanide and heated to reflux overnight. After cooling, the reaction mixture was filtered and concentrated, and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 31 mg of the title compound were obtained (18% of theory).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:20]4[CH2:21][CH2:22][N:23]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:24][CH2:25]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCNCC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)C(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
To a solution of [2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ylmethanone and NEt3 (27 μL, 0.20 mmol) in DCM (5 mL) was added isobutyryl chloride (10 μL, 0.12 mmol) and the resulting mixture stirred at r.t. for 3 h. The reaction mixture was quenched with H2O and extracted with DCM. The combined organic phases were dried (MgSO4) and concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 40-70%) affording 863 (7 mg, 13%). LCMS (method I): RT 4.19 min, [M+H]+ 545.3. 1H NMR (CDCl3, 400 MHz): δ 8.06-8.05 (1 H, m), 7.88-7.81 (1 H, m), 7.39-7.31 (2 H, m), 4.75-4.63 (2 H, m), 4.14-4.02 (5 H, m), 3.93-3.91 (5 H, m), 3.51-3.40 (2 H, m), 3.31-3.40 (1 H, m), 2.84-2.82 (2 H, m), 2.08-1.96 (2 H, m), 1.89-1.62 (4 H, m), 1.49 (3 H, t, J=7.43 Hz), 1.20-1.12 (6 H, m)
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])([CH3:4])([CH3:3])[CH3:2].C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:15]=[C:16]([CH2:17][OH:18])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C=O)cc1-c1ccncc1C(C)(C)O[SiH2]C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CO)cc1-c1ccncc1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 1 h

Procedure:
3-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-4-yl]-4-methoxy-benzaldehyde (160 mg) was dissolved into ethanol (3 mL) and treated with sodium borohydride (85 mg). The reaction mixture was stirred for 1 hour, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield {3-[3-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-4-yl]-4-methoxy-phenyl}-methanol as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:11])=[CH:6][N:5]=1.[F:12][C:13]1([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:26][C:13]2([F:12])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[C:7]([I:11])=[CH:6][N:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Nc1cc(Cl)ncc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(F)(CNc2cc(Cl)ncc2I)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
Sodium hydride (60% by wt) (32.7 mg, 0.817 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (160 mg, 0.629 mmol) in DMF (3930 μL) at room temperature and the mixture was stirred for 10 min. The temperature was raised to 80° C. and tert-butyl 4-fluoro-4-(tosyloxymethyl)piperidine-1-carboxylate (244 mg, 0.629 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 80° C. for 2 hr before further NaH (1.3 eq.) was added after first cooling the reaction to room temperature again. The reaction mixture was heated at 120° C. for 10 hr. After cooling, the solution was partitioned between EtOAc (150 mL) and 1M aqueous NaHCO3. The organic layer was washed with 1M NaHCO3 aq., sat. NaHCO3 and brine, then dried (MgSO4) and concentrated. The residue was dissolved in dichloromethane/hexane and loaded onto a 25+M Biotage silica column. Chromatography, eluting with 1% MeOH in dichloromethane gave partial purification. Further purification by preparative thin layer chromatography, eluting with 16% EtOAc in dichloromethane, gave tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (39 mg, 0.083 mmol, 13%) as a colourless solid.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1.CCOCC>O1CCCC1>[S:10]=[C:24]1[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(N[C@@H]1CCc2ccccc2NC1=S)OCc1ccccc1
Yield: 73.6 %

Procedure:
Add Lawesson's Reagent (12.25 g, 30.29 mmol) to a solution of benzyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (9.4 g, 30.29 mmol) in tetrahydrofuran (470 mL) and stir the reaction under nitrogen for approximately 16 hours at ambient temperature. Remove the precipitate by filtration and discard it. Concentrate the filtrate under reduced pressure and dissolve the residue in ethyl acetate. Wash with water and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure to give a thick, yellow oil. Add ether to the thick oil and scratch it to form a solid. Collect the solid by filtration and wash it with ether. Triturate the solid with ether and collect it by filtration to give the title compound (7.28 g, 74%) as a white solid: MS (m/z): 349 (M+23).