Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:26][OH:27].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[N:26][OH:27])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C=O)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C=NO)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldehyde (3.16 g, 9.48 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (1.27 g, 18.3 mmol) and 2M NaOH (7 mL, 14 mmol). The resulting suspension was stirred overnight at room temperature (18 hours). The mixture was brought to pH 4 using 1M HCl, followed by filtration and water wash. The crystals were dried under vacuum over P205, affording 2.88 g (87%); mp: 114.4°-116.1° C.; 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.10 (b, 2H), 4.03 (t, J=6.2 Hz 2H), 2.71 (bt, 2H), 1.73 (m, 4H), 1.46 (s, 9H), 1.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].Br[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:25][CH2:24][CH2:23][N:8]1[CH2:9][CH2:10][C:5]([C:3]([O:2][CH3:1])=[O:4])([N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12](=[O:15])[CH2:13][CH3:14])[CH2:6][CH2:7]1
Reactant: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCO)CC1
Yield: 96.9 %

Procedure:
A mixture of 4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (7.34 g, 25 mmol), 2-bromoethanol (3.96 g, 32 mmol), sodium carbonate (20.0 g, 189 mmol), and sodium iodide (1.0 g) in acetonitrile (200ml) was heated to reflux for three days. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum yielding an oily residue. The residue was chromatographed on silica gel (250 g; ethyl acetate/hexane; 1:4) to yield 1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (8.1 g, 96%) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][NH:28][N:29]=[C:23]2[N:22]([CH2:30][C:31]([CH3:33])=[CH2:32])[C:21]1=[O:34]>CC(C)=O>[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][N:28]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[N:29]=[C:23]2[N:22]([CH2:30][C:31]([CH3:33])=[CH2:32])[C:21]1=[O:34]
Reactant: C=C(C)Cn1c(=O)n(C)c(=O)c2c[nH]nc21
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Chloromethyl)naphthalene (0.214 ml) and potassium carbonate (0.60 g) were added to a suspension of 5-methyl-7-(2-methyl-2-propenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6[5H,7H]-dione (0.215 g) in acetone (10 ml). The mixture was stirred at room temperature for 16 hours and then heated at reflux for 2 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate:hexane (2:1) followed by recrystallisation from ethyl acetate/hexane to give the subtitle compound (0.062 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:9]=3)[N:14]=[C:13]([CH3:18])[C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 43.1 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (40 mg, 0.039 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (37 mg, 0.078 mmol) and cesium carbonate (952 mg, 2.92 mmol). 6-Bromo-4-(4-chloro-phenyl)-3-methanesulfonyl-2-methyl-quinoline (compound of example 16) (800 mg, 1.95 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.204 g, 2.33 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (350 mg, 43%). MS: m/z=417 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.O>[NH:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NCC1CCNC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
TEA (1.05 mL, 7.5 mmol) was added to a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (1 g, 5 mmol) in DCM (25 mL) at 0° C. Methanesulfonyl chloride (0.43 mL, 5.5 mmol) was then added. After stirring at 0° C. for 2 h, the reaction mixture was diluted with water. The organic phase was separated, dried (MgSO4), filtered and concentrated. The crude material was treated with 1M HCl in MeOH (25 mL) at RT and stirred at RT for 20 h. The volatiles were removed under reduced pressure to afford 0.95 g of 72 as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:20](=[O:23])[CH2:21][CH3:22])[C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH:15]([C:20](=[O:23])[CH2:21][CH3:22])[C:16](=[O:19])[CH2:17][CH3:18])[CH2:12][CH2:13]2)=[CH:24][CH:25]=1
Reactant: CCC(=O)C(CC1CCC(Cc2ccc(OC)cc2)CC1)C(=O)CC
Agent: BrB(Br)Br
Product: CCC(=O)C(CC1CCC(Cc2ccc(O)cc2)CC1)C(=O)CC

Procedure:
It is further contemplated that 4-[4-(4-methoxybenzyl)cyclohexylmethyl]heptane-3,5-dione can be demethylated with boron tribromide according to the procedure of Example 2 to give 4-[4-(4-hydroxybenzyl)cyclohexylmethyl]heptane-3,5-dione [II; Ar is 4-HOC6H4, Y' is CH2, R is C2H5 ].
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.C([C:10]1[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=1)=O.N1CCCCC1>N1C=CC=CC=1>[CH3:20][S:17]([O:16][C:13]1[CH:12]=[CH:11][C:10](/[CH:3]=[CH:2]/[C:1]([OH:7])=[O:6])=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Oc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 90 °C
Yield: 57.4 %

Procedure:
Malonic acid (7.80 g, 74.92 mmol) was added to a solution of the crude methanesulfonic acid 4-formylphenyl ester (10 g, 49.95 mmol), which was synthesized in the preceeding step, and piperidine (0.7 ml, 7.09 mmol) in pyridine (50 ml). The reaction mixture was heated to 90° C. for 2.5 h. It was cooled to room temperature. Concentrated hydrochloric acid/ice (400 ml/100 ml) was added. The precipitation was filtered off and washed with a 10% aqueous solution of acetic acid (200 ml). It was dried in vacuo to give 6.95 g of (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:21]([F:29])[CH:22]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Fc1cc(Br)c2cn[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.3 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indazole (1.0 g, 4.65 mmol) in dichloromethane (50 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.29 g, 9.31 mmol), pyridine (0.75 mL, 9.28 mmol), copper acetate (1.26 g, 6.96 mmol) and powdered 4A molecular sieves (2 g). The reaction mixture was stirred at room temperature in the presence of air for 4 days. Celite was added to the mixture and stirred for 5 mins, then the mixture was filtered through a pad of celite and then the filtrate was washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-100% dichloromethane in hexane to yield the title compound (D7) (779 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH:11]1([C:17]2([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CC(N(C)C)=O>[CH:11]1([C:17]2([C:23]([O:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=3)=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cc1ncc(O)cn1
Reactant: O=C(Cl)C1(C2CCCCC2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ncc(OC(=O)C2(C3CCCCC3)CCCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To an ice-cooled mixture of 2-methyl-5hydroxypyrimidine (0.9 g) and sodium hydride 80% (0.24 g) in dimethylacetamide (15 ml), a solution of 1-cyclohexylcyclohexane-1-carbonyl chloride (1.68 g) in dimethylacetamide (10 ml) was added. The mixture was then stirred at room temperature for 1 hour, then filtered and evaporated in vacuo. The residue was taken up with ethyl acetate, which was washed with water and dried. Evaporation of the solvent and column chromatography (cyclohexane/ethyl acetate 9:1) afforded 1.2 g of 2-methylpyrimidin-5-yl 1-cyclohexylcyclohexane-1-carboxylate. M.p. 52°-55° C. According to the procedure above described the following compound was also prepared, 2-methylpyrimidin-5-yl α-cyclopentylphenyl glicolate hydrochloride. M.p. 132°-138° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[OH:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[OH:36][C@H:37]1[CH2:41][CH2:40][N:39]([C:30](=[O:32])[CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH3:33])[CH2:38]1
Reactant: O[C@H]1CCNC1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Product: CC(C(=O)N1CC[C@H](O)C1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and (S)-3-hydroxypyrrolidine. LCMS (M+H)+: m/z=553.3
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:36][CH2:35][CH2:34][N:25]1[C:26](=[O:33])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]1=[O:23])[CH:19]([CH3:20])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc2c(c1)nc(C(N)C(C)C)n2Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)nc(C(NCCCN1C(=O)c3ccccc3C1=O)C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamine (0.56 mmol) and 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (114 mg, 0.56 mmol) in dry DCM (3 mL) at room temperature, was added sodium triacetoxyborohydride (119 mg, 0.56 mmol). After 10 min., acetic acid (34 μl, 0.56 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give crude material that was used in step 7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-3-chlorophenol (1 g, 4.82 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.332 g, 9.64 mmol) and benzyl bromide (0.630 ml, 5.30 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 297 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:29]([O:36][C:37]([NH:39][CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:2][O:3][CH:4]=[C:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[CH2:41][CH2:42]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Tetrahydrofuran (280 ml) was added to (methoxymethyl)triphenylphosphonium chloride (27.8 g, 81.1 mmol) and a solution (50.0 ml, 80.0 mmol) of 1.6M n-butyllithium in n-hexane was dropwise added at -40° C. over 30 minutes, which was followed by stirring for one hour. Then, a solution of 4-(benzyloxycarbonylamino)cyclohexanone (20.0 g, 81.0 mmol) dissolved in tetrahydrofuran (200 ml) was dropwise added over 30 minutes. The mixture was warmed to room temperature and stirred for 3.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the extract and the organic layer were combined. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give 7.02 g of 4-(benzyloxycarbonylamino)cyclohexylidenemethyl methyl ether as a colorless solid (32%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([Cl:13])=[O:9]
Reactant: O=C(O)C1CCCCO1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5H, m), 2.02-2.19 (1H, m), 3.46-3.66 (1H, m), 3.96-4.12 (1H, m), 4.24 (1H, dd, J=9.14, 3.20 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2ocnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2ocnc2c1
Temperature: 25 °C
Yield: 12.6 %

Procedure:
Combine 5-methyl-benzoxazole (0.5 g, 3.75 mmol), NBS (0.7 g, 3.93 mmol), AIBN (60 mg, 0.37 mmol), chloroform (10 mL) and reflux for 1 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1 and 7:3) to obtain the title compound as a white solid (0.1 g, 13%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:2].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][O:14][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C=O)ccc1OCC(=O)OC(C)(C)C
Yield: 97.3 %

Procedure:
Phenol 2c (1.0 g, 5.2 mmol), t-butyl bromoacetate (0.84 mL, 5.2 mmol), and potassium carbonate (0.79 g, 5.7 mmol) were heated at 65° C. in DMF (8 mL) overnight. After solvent removal, the mixture was diluted with EtOAc and extracted with water (3×), then brine. Drying (MgSO4) and removal of solvent gave a clear yellow oil (1.56 g). 1H-NMR(300 MHz, CDCl3): 9.93 (s, 1H), 8.35 (d, 1H, J=2 Hz), 7.99 (dd, 1H, J=9,2 Hz), 6.95 (d, 1H, J=9 Hz), 4.71 (s, 2H), 4.41 (q, 2H, J=7 Hz), 1.48 (t, 3H, J=7 Hz). Anal. Calc'd for C16H20O6 : C, 62.33; H, 6.54; Found: C, 62.05; H, 6.58.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([NH:14][CH3:15])=O)=[CH:2]1.B.CSC>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:12][NH:14][CH3:15])=[CH:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1c[nH]c2ccccc12
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1c[nH]c2ccccc12

Procedure:
In an alternate procedure, 3-(1H-Indol-3-yl)-N-methyl-3-phenyl-propionamide (0.400 g) was reduced by refluxing overnight in THF (20 ml) with excess borane-dimethylsulfide to yield [3-(1H-Indol-3-yl)-3-phenyl-propyl]-methyl-amine, which was converted to an oxalate salt (mp 123.7-134.1° C.).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:12]1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[N:25][C:16]=1[NH:15][C@H:13]1[CH2:14][C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH2:12]1
Reactant: Clc1ncnc2c1ncn2[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ncnc3c2ncn3[C@H]2C[C@H](Nc3ncc4ccccc4n3)C2)cc1
Temperature: 120 °C

Procedure:
N-(Trans-3-(6-chloro-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (example 21, 0.110 g, 0.313 mmol), tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), (4-methoxycarbonylphenyl)boronic acid (0.073 g, 0.406 mmol), and cesium carbonate (0.357 g, 1.094 mmol) were suspended in a mixture of dioxane (1.25 mL) and water (0.15 mL) and heated in the microwave to 120° C. for 25 minutes. The crude was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-3% methanol in dichloromethane gradient) gave the desired methyl 4-(9-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-9H-purin-6-yl)benzoate (0.0531 g, 0.118 mmol, 37.6% yield). M+1: 452.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.89 (ddd, J=13.60, 8.51, 4.89 Hz, 2 H) 3.15-3.33 (m, 2 H) 3.98 (s, 3 H) 4.89-5.00 (m, 1 H) 5.44 (quin, J=7.34 Hz, 1 H) 7.30-7.35 (m, 1 H) 7.65 (d, J=8.41 Hz, 1 H) 7.69-7.81 (m, 2 H) 8.24 (d, J=8.41 Hz, 2 H) 8.45 (s, 1 H) 8.84 (d, J=8.41 Hz, 2 H) 9.01-9.14 (m, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11]CC)=[O:10])[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(=O)O)nn1C
Yield: 46.9 %

Procedure:
Ethyl 5-ethyl-1-methylpyrazole-3-carboxylate (6.86 g) in ethanol (70 ml) was treated with sodium hydroxide (1.58 g) in water (30 ml) and heated under reflux for 6 h. The solution was concentrated and the aqueous phase washed with ethyl acetate before adding dichloromethane (50 ml). The solution was acidified with 5M hydrochloric acid, and the mixture exhaustively extracted with dichloromethane. The remaining undissolved solid was filtered off suspended in water and the pH adjusted to 6 with saturated sodium hydrogen carbonate. The solution was again extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate and concentrated to give the title compound as a white solid, (2.72 g, 47%); (Found: M+, 154.0742. C7H10N2O2 requires M, 154.0742); nmax (CH2Cl2) 3689 and 1760 cm- ; dH (CDCl3) 1.30 (3H, t, J7.4 Hz), 2.64 (2H, q, J7.4 Hz), 3.88 (3H, s) and 6.65 (1H, s).