Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([O:22][CH3:23])[C:20]#[CH:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][O:22][CH3:23])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#CCOC
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: 70 °C
Yield: 83.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with methyl propargyl ether (0.71 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (503 mg, 83.8%) as an amber oil: EI-HRMS m/e calcd for C19H24O3 (M+) 300.1725, found 300.1728.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]1[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:14])(C)(C)C.C(N(CC)CC)C.ClC(O[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=O>C(Cl)Cl>[CH2:52]([O:12][C:13]([N:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]1[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]([OH:38])=[O:37])=[O:14])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2C(C)(C)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(C(=O)OCc2ccccc2)C(c2cc(Cl)ccc2OCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (0.92 mL, 11.8 mmol, 20.0 eq.) was added to a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (280 mg, 0.59 mmol, 1.0 eq.) in DCM (1 mL). The resulting mixture was stirred at r.t. during 5 hours. The mixture was concentrated in vacuo. To an-ice cooled suspension of the residue and triethylamine (0.41 mL, 2.95 mmol, 5.0 eq.) in DCM (1 mL), benzyl chloroformate (0.18 mL, 1.18 mmol, 2.0 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 18 hours. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×2 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (1 mL), 1M aq. NaOH soln. (1 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)O)[CH2:10][CH2:9]1.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)[CH2:10][CH2:9]1
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.76 ml (9.82 mmol) of trifluoroacetic acid was added to 1.77 g (8.19 mmol) of the compound from Example 149A and 1.45 g (8.19 mmol) of the compound from Example 8A in 91 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 890 mg (29% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=[CH:16][CH:15]=1.C(OCC)=C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH:15]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH2:16]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: OCCCCOCc1ccccc1
Agent: [Pd+2]
Agent: C=COCC
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=COCCCCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
Under reaction conditions as described in J. Org. Chem. 1997, 62, 1560, {[4-(vinyloxy)butoxy]methyl}benzene was obtained using 4-(benzyloxy)butan-1-ol as a starting material. That is, 1,10-phenanthroline (1.00 g) and palladium(II) acetate (2.50 g) were added to a mixture of ethyl vinyl ether (25 mL) and dichloromethane (15 mL), followed by stirring for 15 minutes, and then 4-(benzyloxy)butan-1-ol (5.00 g) was added thereto, followed by stirring at room temperature for 60 hours. The reaction mixture was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=95/5) to obtain {[4-(vinyloxy)butoxy]methyl}benzene (3.24 g).
Reaction SMILES: [CH2:1]([C:3]1[C:7](=[O:8])[O:6][NH:5][C:4]=1[CH2:9][CH2:10][CH3:11])[CH3:2].O=C(Cl)[O:14][C:15](Cl)(Cl)[Cl:16]>ClCCl>[CH2:1]([C:3]1[C:7](=[O:8])[O:6][N:5]([C:15]([Cl:16])=[O:14])[C:4]=1[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCc1[nH]oc(=O)c1CC
Solvent: ClCCl
Product: CCCc1c(CC)c(=O)on1C(=O)Cl
Temperature: 0 °C
Reaction time: 6 h

Procedure:
At 0° C., 15 g (96.65 mmol) of 4-ethyl-3-propyl-5(2H)-isoxazolone in 150 ml of dichloromethane are admixed with 27.81 g (144.98 mmol) of diphosgene, and the mixture is then stirred at 0° C. for 6 h. To remove excess phosgene, argon was passed through the reaction mixture at RT for 1 h, the exhaust gas being neutralized by sodium hydroxide. The solution was concentrated and the product was distilled under reduced pressure. B.p.mbar 125-30° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:4](O)[CH2:5][CH3:6])[CH3:2].C#CC([OH:20])CCC.C(O)CCCCCCC/C=C\CCCCCCCC>>[CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH:5]([OH:20])[CH3:6])[CH3:2]
Reactant: CCCCCCC(CC)C(O)CC
Reactant: C#CC(O)CCC
Agent: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCC(CC)CC(C)O

Procedure:
4-ethyl-3-decanol; 1-hexyn-3-ol and oleyl alcohol.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[N:25]=[C:24]([O:26][CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)[CH:23]=[N:22][CH:21]=4)=[CH:18][N:17]([S:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)(=[O:42])=[O:41])[C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[N:25]=[C:24]([O:26][CH:27]5[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]5)[CH:23]=[N:22][CH:21]=4)=[CH:18][N:17]([S:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)(=[O:41])=[O:42])[C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7]1
Reactant: CCOC(=O)Cn1cc(-c2cnc3c(c2)c(-c2cncc(OC4CCN(C(=O)OC(C)(C)C)CC4)n2)cn3S(=O)(=O)c2ccccc2)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(-c5cnn(CCO)c5)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of tert-butyl 4-({6-[5-[1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)piperidine-1-carboxylate (0.10 g, 0.15 mmol) in tetrahydrofuran (2 mL) was added lithium aluminium hydride (11 mg, 0.29 mmol) (CAUTION: GAS EVOLUTION). The reaction mixture was stirred at room temperature for 2.5 h then cooled in an ice bath. Sodium sulfate decahydrate (0.32 mL, 1.5 mmol) was added to the reaction mixture slowly (CAUTION: GAS EVOLUTION). The reaction mixture was warmed to room temperature and filtered through celite. The filtrate was concentrated to a crude solid and purified by reverse phase HPLC to afford tert-butyl 4-({6-[5-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)piperidine-1-carboxylate. LRMS (ESI) calculated for C32H35N7O6S [M+H]+, 646.2; found 646.2.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH:24]=[CH2:25])[O:12][C@H:11]1[N:26]1[C:48]2[N:47]=[C:46]([Cl:49])[N:45]=[C:30]([NH:31][N:32]3[CH2:37][CH2:36][CH:35]([S:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:34][CH2:33]3)[C:29]=2[N:28]=[CH:27]1)(=O)C1C=CC=CC=1.NN1CCC(SC2C=CC=CC=2)CC1.N>CO>[Cl:49][C:46]1[N:45]=[C:30]([NH:31][N:32]2[CH2:33][CH2:34][CH:35]([S:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:36][CH2:37]2)[C:29]2[N:28]=[CH:27][N:26]([C:48]=2[N:47]=1)[C@@H:11]1[O:12][C@H:13]([CH:24]=[CH2:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: C=C[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Agent: NN1CCC(Sc2ccccc2)CC1
Solvent: CO
Product: C=C[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
2',3'-Di-O-benzoyl-2-chloro-5'-deoxy-5'-methylene-N-(4-phenylthio-1-piperidinyl)adenosine, prepared as described in Example 25 from 2,6-dichloro-9-(5'-deoxy-2',3'-di-O-benzoyl-5'-methylene-β-D-ribofuranosyl)-9H-purine (1.0 g, 1.9 mmol) and 1-amino-4-phenylthiopiperidine (0.44 g, 2.1 mmol), was dissolved in methanol (20 ml) and sat. methanolic ammonia (2.5 ml) was introduced. The reaction mixture was stirred at ambient temperature for 18 h, evaporated and purified by flash chromatography eluting with a mixture of dichloromethane and ethanol (50:1) to provide the title 2-chloro-5'-deoxy-5'-methylene-N-(4-phenylthio-1-piperidinyl)adenosine (0.27 g, 29%) as a foam, 1H-NMR (400 MHz, DMSO-d6) δ1.70 (2H, br q, piperidine C--H), 1.99 (2H, br d, piperidine C--H), 2.77 (2H, br m, piperidine C--H), 3.06 (2H, br m, piperidine C--H), 4.07 (1H, q, H-3'), 4.32 (1H, dt, H-2'), 4.58 (1H, m, H-4'), 5.20 (1H, dd, C=C--H), 5.29 (1H, d, C=C--H), 5.39, 5.56 (2H, 2d, 2'-and 3'-OH), 5.86 (1H, d, H-1'), 6.07 (1H, m, C=C--H), 7.23-7.45 (5H, 3 m, Ar--H), 8.36 (1H, s, H-8), 9.34 (1H, s, N--H). HPLC retention time 13.46 min. (gradient elution over 30 min; 25-45% acetonitrile/0.1% ammonium sulfate in water), purity 100% at 250 nm).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].[I-:16].[K+].[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[I-:16].[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][P+:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COCCOCCOCCOCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCOCCOCCOCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -20 °C

Procedure:
To a solution of 1-chloro-3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}propane (2.4 g) in dry acetonitrile (30 ml) was added potassium iodide (1.66 g), and triphenylphosphine (2.63 g) and the suspension heated at reflux for 24 hours. The cooled solution was filtered and the filtrate evaporated under reduced pressure to give a colourless oil which on cooling to -20° C. gave a white oily solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)[CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][C:2]1[N:7]=[C:6]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)[N:5]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)[CH:3]=1
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)nc(Oc2ccnc(C(F)(F)F)c2)n1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A mixture of 0.63 g (2.4 mmol) of 6-methyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-chloropyrimidine, 0.39 g (2.4 mmol) of 4-hydroxy-2-trifluoromethylpyridine and 0.66 g (4.8 mmol) of K2CO3 in 20 ml of acetonitrile stirred under reflux for 8 h and then allowed to stand at RT overnight. The mixture is poured into 40 ml of water and extracted four times with in each case 20 ml of CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. Chromatographic purification on silica gel using heptane/ethyl acetate (7:3) gives 0.8 g (85%) of 6-methyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-(2-trifluoromethylpyridin-4-yloxy)pyrimidine.
Reaction SMILES: [CH3:1][N:2]([S:16]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:3][CH2:4]OS(C1C=C(C)C=CC=1)(=O)=O.[CH2:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH2:26]([N:33]1[CH2:38][CH2:37][N:36]([CH2:4][CH2:3][N:2]([CH3:1])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)(=[O:17])=[O:18])[CH2:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1cccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2cccc(C)c2)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(S(=O)(=O)N(C)CCN2CCN(Cc3ccccc3)CC2)c1

Procedure:
A solution of D1 (22 g, 89 mmol) and N-benzylpiperazine (15.7 g, 89 mmol) was heated to reflux in toluene for 96 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo and the residue was purified by chromatography on silica gel to afford the title compound. MH+ 388.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[Na+].O>CO>[OH:13][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C(=O)c1ccccc1
Yield: 62.8 %

Procedure:
To a solution of 2-bromo-1-phenylpropan-1-one (6.0 g, 28.2 mmol) in methanol (50 mL) was added sodium formate (7.66 g, 113 mmol) and the mixture was heated under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (2.66 g, yield 63%) as a colorless oil.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:24]3[CH2:10][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:12])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.108 g, 0.5 mmol), 4-(4-fluoro-phenoxy)-benzylamine (0.115 g, 0.5 mmol), and K2CO3 (0.235 g, 1.7 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[4-(4-fluoro-phenoxy)-benzyl]-2,3-dihydro-isoindol-1-one (0.100 g, 60%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.29 (s, 2H), 4.78 (s, 2H) 6.83-7.56 (m, 1H), 7.89 (d, 1H). GC-MS: m/z 333 (M)+.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([OH:10])=[N:3][CH:2]=1.C(OC(=O)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH:28]=[O:29])[C:22]=1[F:30])C1C=CC=CC=1>>[NH2:20][C:21]1[C:22]([F:30])=[C:23]([C:28]([C:9]2[C:5]3[C:4]([OH:10])=[N:3][CH:2]=[N:1][C:6]=3[NH:7][CH:8]=2)=[O:29])[C:24]([F:27])=[CH:25][CH:26]=1
Reactant: Oc1ncnc2[nH]ccc12
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(O)c23)c1F

Procedure:
(3-Amino-2,6-difluoro-phenyl)-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone 39 is synthesized in two steps from 7H-pyrrolo[2,3-d]pyrimidin-4-ol 37 and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester 33 as shown in Scheme 1g.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:42]=2[NH:41][CH:40]=[CH:39]3)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]4[C:42]=3[NH:41][CH:40]=[CH:39]4)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1(C)OB(c2cccc3cc[nH]c23)OC1(C)C
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc4cc[nH]c34)nc12
Temperature: 85 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 117 μmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (37.0 mg, 152 μmol), potassium carbonate (16.2 mg, 117 μmol) were combined in a reaction tube with a teflon-threaded seal, dioxane (2.5 mL) and water (0.5 mL) were added, then the mixture degassed with nitrogen for 1 min. Tetrakis(triphenylphosphine)palladium(0) (13.5 mg, 11.7 μmol) was added, nitrogen was bubbled through for 1 minute, then the reaction was heated to 85° C. for 6 h, and then at 75° C. for an additional 15 h. The reaction mixture was cooled, concentrated in vacuo, and the residue purified by chromatography (silica, 1-15% ethyl acetate in hexanes) to give N-tert-butyl-2-(1H-indol-7-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (54 mg) as an oil which slowly crystallized. MS (M+H)+=464.2.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CNC(=O)c1ccc2c(c1)C(C1CCCCC1)=NCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNC(=O)c1ccc2c(c1)C(C1CCCCC1)NCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-cyclohexyl-N-isobutyl-3,4-dihydroisoquinoline-7-carboxamide (689 mg) was dissolved in MeOH (12 mL). Sodium borohydride (100 mg) was added to the reaction mixture, followed by stirring at room temperature for 5 hours. The solvent was evaporated. To the resulting residue were added water and chloroform. The residue was extracted with chloroform and dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 1-cyclohexyl-N-isobutyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24]C=1.C1(C(Cl)=O)CCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:27]4[CH2:24][CH2:25][CH2:26]4)[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: c1ccccc1
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1S2
Agent: O=C(Cl)C1CCC1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Clc1ccc2c(c1)C(=C1CCN(CC3CCC3)CC1)c1ccccc1S2

Procedure:
Similarly, 6.3 g. (0.02 mol) of 4-(2-chloro-9-thioxanthenylidene)piperidine in 30 ml. of benzene is treated with a solution of 1.2 g. (0.01 mol) of cyclobutylcarboxylic acid chloride in 10 ml. of benzene. Following the above workup procedure, the intermediate amide is reduced with 1.5 g. (0.04 mol) of lithium aluminum hydride in 50 ml. of ether. After isolation of the amine product, the ether is evaporated in vacuo and a hexamate salt formed of 4-(2-chloro-9-thioxanthenylidene)-1-cyclobutylmethylpiperidine, m.p. 180°-182° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@:10]2([NH2:22])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C.O[Li].O.Cl>C1COCC1.O.CO>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OCc3ccccc3)[C@@](N)(C(=O)OCc3ccccc3)[C@@H]21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccccc1)[C@@H]2C(=O)O
Temperature: 23 °C
Yield: 73.2 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-amino-3-benzyloxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-3) (50 mg, 0.122 mmol) and LiOH.H2O (13 mg, 0.30 mmol) in THF (4 mL), H2O (2 mL) and MeOH (0.4 mL) was stirred at 23° C. for 36 h. The solution was acidified with conc. HCl and evaporated to dryness. The remaining pale yellow solid was suspended in EtOH, filtered, washed with more EtOH and the filtrate was evaporated to dryness. The residue was dissolved in EtOH (1 mL) and propylene oxide (1 mL) and refluxed for 3 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-2-amino-3-benzyloxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-10) (26 mg, 72%) as a white solid. 1H-NMR (250 MHz, D2O) □1.57 (1H, t, J=3.5 Hz), 1.97 (2H, m), 2.13 (1H, ddd, J=12.5, 8,3.5 Hz), 2.35 (1H, dd, J=12.5, 7 Hz), 3.73 (1H, dd, J=8, 7 Hz), 4.51 (2H, s), 7.36 (5H, bm); MS[ISN] 290 [(M-H)- ]; mp>250° C.; □D20 -5.69° (c=0.25, H2O).