Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.Br[CH2:25][CH2:26][CH2:27][OH:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:25][CH2:26][CH2:27][OH:28])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: OCCCBr
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCCO)(c1ccccc1)C(=O)N2
Temperature: 60 °C
Yield: 40.8 %

Procedure:
A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one (1.5 g, 5 mmol), 3-bromopropan-1-ol (1.3 g, 10.0 mmol), potassium iodide (0.16 g, 1 mmol) and potassium carbonate (1.3 g, 10.0 mmol) in THF (50 mL) was heated at 60° C. for 5 hours in a capped pressure tube. The mixture was then cooled to room temperature and diluted with ethyl acetate (20 mL) and extracted with water (2×20 mL) and brine (20 mL). Aqueous layers were back washed with ethyl acetate (20 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product (0.74 g, 41%). 1H NMR (400 MHz, DMSO-d6): δH 10.65 (s, 1H), 7.23-7.36 (m, 7H), 7.00 (d, J=8.0 Hz, 1H), 4.39 (m, 1H), 3.31-3.33 (m, 2H), 2.37 (s, 3H), 2.18-2.28 (m, 2H), 2.16 (s, 3H), 1.21-1.27 (m, 1H), 1.02-1.06 (m, 1H) MS (ESI) m/e [M+1]+ 363.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([C:11]1[S:10][C:9]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3)sc2c1
Yield: 52 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and benzoyl chloride were converted to the title compound by the procedure of Example 1 in 52% yield, after crystallization from methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]([C:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Na+].[OH-].[Na+]>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[N:12]=[CH:13][CH:14]=[N:15]2)[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)[O-])c(-n2nccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C(=O)O)c(-n2nccn2)c1

Procedure:
(sodium 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinate). To a solution of the title compound of Step A (489 mg, 2.6 mmol) in EtOH (7 mL) was added 4 N NaOH (660 μL, 2.6 mmol). The mixture was heated at 100° C. for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C9H8N4O2, 204.1. m/z found 205.0 [M+H]+.
Reaction SMILES: C1C2C=CC3C4C=CC=CC=4C=CC=3C=2OC=1C=O.[CH:20]1[C:21]2[CH:38]=[CH:37][C:36]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH:29]=[CH:28][C:27]=3[C:22]=2[S:23][C:24]=1[CH2:25][OH:26]>C(Cl)Cl.CCCCCC>[CH:20]1[C:21]2[CH:38]=[CH:37][C:36]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH:29]=[CH:28][C:27]=3[C:22]=2[S:23][C:24]=1[CH:25]=[O:26]
Reactant: OCc1cc2ccc3c4ccccc4ccc3c2s1
Agent: O=Cc1cc2ccc3c4ccccc4ccc3c2o1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc2ccc3c4ccccc4ccc3c2s1
Yield: 82.9 %

Procedure:
Using the procedure outlined in 14B, phenanthro[1,2-b]thiophene-2-methanol (16A) gave a 82.9% yield of phenanthro[1,2-b]thiophene-2-carbaldehyde, mp 209°-210°, (C,H,S), (CH2Cl2 /hexane).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[O:10][CH3:11].[Si](O[CH:20]1[CH2:24][C:23](=[O:25])[C:22]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[CH:21]1)(C(C)(C)C)(C)C.[O:38]1CCCC1>>[OH:38][CH:24]1[C:23](=[O:25])[C:22]([C:26]2[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=2)=[C:21]([C:7]2[CH:6]=[CH:5][C:4]([O:10][CH3:11])=[C:3]([Cl:2])[CH:8]=2)[CH2:20]1
Reactant: COc1ccc(Br)cc1Cl
Reactant: C1CCOC1
Reactant: COc1cc(C2=CC(O[Si](C)(C)C(C)(C)C)CC2=O)cc(OC)c1OC
Agent: [Mg]
Product: COc1ccc(C2=C(c3cc(OC)c(OC)c(OC)c3)C(=O)C(O)C2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of magnesium turnings (0.31 g, 13.1 mmol), 2-chloro-4-bromoanisole (3.00 g, 13.5 mmol), 4-tert-butyldimethysilyloxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-2-en-1-one (2.58 g, 6.84 mmol) and dry tetrahydrofuran (35 ml) under nitrogen was stirred at room temperature for 4 h. Reaction was then quenched with dil hydrochloric acid (30 ml), tetrahydrofuran was removed under reduced pressure and the residual reaction mixture was extracted with ethyl acetate (3×35 ml), washed with water (2×20 ml) and dried over sodium sulfate. Concentration and purification by column chromatography over silica gel (eluent-6% acetone in pet ether) afforded the alcohol of the formula (4A)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:26]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].C([O-])(O)=O.[Na+]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:31][C:28]1[CH:29]=[CH:30][C:25]2[O:24][N:23]=[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:26]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(F)cc34)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(F)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.3 g (5 mmol) of trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester is solved in dichloromethane (15 mL) and trifluoroacetic acid is added at 0° C. (10.7 mL, 46 mmol) and the mixture is stirred at room temperature overnight. NaHCO3 is slowly added until pH 9 and the mixture extracted 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield 1.86 g (5.3 mmol, 100%) of a white solid that was used without purification on the next steps. MS (m/e): 346.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:19]([O:18][C:13]([C:14]1([CH3:16])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(C)=O
Reactant: Oc1ccccc1-n1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C)Oc2ccccc2-n2cccc21
Reaction time: 18 h

Procedure:
A solution of the compound of formula 2, N-(2-hydroxyphenyl)pyrrole (18 g), described in Example 1, ethyl pyruvate (13 g) and p-toluenesulfonic acid (1.8 g) in benzene (1.2 1) is stirred and heated at reflux with a Dean-Stark water trap for 30 min. The reaction mixture is allowed to cool and stand at room temperature for 18 hr. The mixture is filtered and the filtrate is washed with 5% NaHCO3, water, saturated brine solution, and then dried (MgSO4). The solvent is evaporated and the remaining material is adsorbed on a silica gel column. Elution with chloroform gives 4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-carboxylic acid ethyl ester, νmaxCHCl3 1,735, 1,605, 1,510, 1,345, 1,125, 1,095 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22]C)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.CC(O)=O.Br>O.[OH-].[Na+]>[NH2:21][C:19]1[CH2:18][O:17][CH2:16][C@:15]2([C:14]3[CH:13]=[C:12]([OH:22])[N:11]=[CH:10][C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[N:20]=1
Reactant: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(O)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
(S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.611 g, 1.624 mmol) was dissolved in HOAc (6.14 mL, 107 mmol). Hydrobromic acid (48% aq.; 6.06 mL, 53.6 mmol) was added and the reaction was stirred at 100° C. for two hours. The reaction was diluted with water, slowly neutralized to pH 7 with 6N NaOH, and stirred overnight, during which a light pink solid crashed out of solution. The solution was filtered, and the solid was air dried to afford (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.554 g, 1.530 mmol, 94% yield) as an off-white solid. [M+H]+=363.9
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]1[NH:12][C:11](=O)[CH2:10][NH:9][C:8]1=O.C1COCC1.CSC>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]1[CH2:8][NH:9][CH2:10][CH2:11][NH:12]1
Reactant: COc1cccc(CC2NC(=O)CNC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cccc(CC2CNCCN2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
To a 100-mL round-bottomed flask was added 3-(3-methoxybenzyl)-2,5-piperazinedione (201 mg, 0.858 mmol), 5 mL of THF and BH3.DMS (0.326 mL, 3.43 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was stirred at 70° C. for 18 h and then diluted with 1N NaOH (12 mL) and extracted with CH2Cl2 (2×50 mL). The organic extracts were washed with saturated aqueous NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude 2-(3-methoxybenzyl)piperazine (152 mg) as a colorless tar.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:32])[C:10](=[O:31])[C@@H:11]([NH:23]C(=O)OC(C)(C)C)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=1>C(Cl)Cl>[NH2:23][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=1)[C:10]([N:9]([CH3:8])[CH3:32])=[O:31]
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(C[C@H](N)C(=O)N(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to (S)-tert-butyl 1-(dimethylamino)-3-(4-isopropoxyphenyl)-1-oxopropan-2-ylcarbamate in methylene chloride (2 mL). After stirring for 1 h., the reaction was concentrated under reduced pressure to give the crude product, (2S)-2-amino-3-(4- isopropoxyphenyl)-N,N-dimethylpropanamide (40 mg, 100%). Analytical LCMS (M+H)+: m/z=251.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[N:12]=[N:13][C:14]([CH:17]=[CH2:18])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:17]([C:14]1[N:13]=[N:12][C:11]([NH:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:20])[CH3:19])=[CH:16][CH:15]=1)[CH3:18]
Reactant: [H][H]
Reactant: C=Cc1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Yield: 10 %

Procedure:
The isolated product from Step 1 was dissolved in ethanol (10 mL) and transferred to a 20 dram vial. Palladium (10% on carbon, 10 mg) was then added, and the reaction was stirred under 60 psi of hydrogen for 3 days. The reaction was then filtered, concentrated, and purified by reverse phase column chromatography to afford 3 mg (10%) of 6-ethyl-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine as a clear oil, m/z=274 [M+H].
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([O:22]CC)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH3:26][CH2:27]OCC>CC(C)=O>[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=1)([O-:22])(=[O:21])=[O:20].[CH2:1]([S:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N+:8]=1[CH2:26][CH3:27])[CH3:2]
Reactant: CCSc1nc2ccccc2s1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOCC
Solvent: CC(C)=O
Product: CCSc1sc2ccccc2[n+]1CC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 83 %

Procedure:
2-(Ethylthio)benzothiazole (1062 g, 0.056 mol) and ethyl p-toluensulfonate (11.15 g, 0.056 mol) were heated at 140°-167° C. for 2 hours. The mixture cooled and was dissolved in acetone. The acetone solution was poured into 400 ml anhydrous ether to yield 18.19 g (83%) of gummy solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])[CH3:13].[OH-].[Ba+2].[OH-]>C(O)C>[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])/[CH:13]=[CH:7]/[C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)C(C)C
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(/C=C/C(=O)C(C)C)cc1
Yield: 89.6 %

Procedure:
A solution of p-tolualdehyde (1 mL, 8.48 mmol), 3-methyl-2-butanone (1.81 mL, 16.96 mmol) and barium hydroxide (0.2 g, 1.17 mmol) in ethanol (4 mL) were mixed and the reaction mixture was heated at reflux for 1 hour. After cooling the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried (Mg2SO4), filtered and evaporated to give 1.43 g of trans-4-methyl-1-p-tolyl-pent-1-en-3-one (90%) and used without further purification in the next step (step i). 1H NMR (300 MHz; CDCl3): 1.16 (d, J=7.2 Hz, 6 H), 2.35 (s, 3 H), 2.92 (m, 1 H), 6.79 (dd, J=16.0 Hz, 1 H), 7.19 (d, J=7.5 Hz, 1 H), 7.43 (d, J=8.1 Hz, 1 H), 7.28 (d, J=16.2 Hz, 1 H).
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:46]=3[N:47]=[CH:48][N:49]=2)[C@@H:16]2[O:45][C@H:35]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@@H:26]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:17]2[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])C2C=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[N:50]1([C:11]2[N:49]=[CH:48][N:47]=[C:46]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:16]2[O:45][C@H:35]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@@H:26]([O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:29])[CH3:30])[C@H:17]2[O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 85.4 %

Procedure:
As described for the synthesis of 6-(morpholin-1-yl)-9-[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuranosyl]-purine, this morpholino derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-inosine (27) (71.8 mg, 0.099 mmol), and morpholine (17.5 μL, 0.200 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at room temperature over 1 h. No additional purification was needed and 57.5 mg (85% yield) of the title compound was obtained. Rf (3% MeOH in CH2Cl2)=0.68. 1H NMR (500 MHz, CDCl3): δ 8.33 (s, 1H, Ar—H), 8.03 (s, 1H, Ar—H), 6.03 (d, 1H, H-1′, J=5.4), 4.72 (t, 1H, H-2′, J=4.9), 4.32-4.29 (br m, 5H, H-3′ and 2CH2), 4.11 (q, 1H, H-4′, J=3.6), 4.02 (dd, 1H, H-5′, J=11.2, 4.4), 3.83 (t, 4H, 2CH2, J=4.6), 3.77 (dd, 1H, H-5′, J=11.2, 3.2), 0.95, 0.93, 0.80 (3 s, 27H, tert-Bu), 0.124, 0.12, 0.104, 0.10, −0.05, −0.22 (6 s, 18H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 153.9, 152.2, 150.9, 137.7, 120.5, 88.1, 85.4, 75.4, 72.1, 67.0, 62.6, 45.6, 26.1, 25.8, 25.7, 18.5, 18.1, 17.9, −4.4, −4.7, −5.0, −5.4, −5.41.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:33][C:29]1[CH:30]=[C:31]([F:32])[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cc(Cl)cnc1Br
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloro-3-fluoropyridine. MS (ESI) 454 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1)[CH3:15]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 g (406 mmol) of 3-aminobenzyl alcohol are suspended in 750 ml of dichloromethane under a nitrogen atmosphere, the mixture is stirred at room temperature for 30 min and subsequently cooled to 0° C. 49 g (452 mmol) of ethyl chloroformate are slowly added dropwise. After the addition, the reaction mixture is stirred for 20 h and at the same time slowly warmed to room temperature. 300 ml of 1M potassium carbonate solution are added to the suspension formed (evolution of gas!). The organic phase is separated off, the aqueous phase is extracted with 200 ml of dichloromethane, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, and the solvent is removed by distillation.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].O.NN>C(O)C.C(Cl)Cl>[NH2:3][O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15]
Reactant: C[C@@H](CON1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C[C@@H](CON)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
To a solution of tert-butyl {(1S)-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]-1-methylethyl}carbamate 58 (1.2 g, 3.74 mmol) in a mixture of ethanol (3 mL) and DCM (20 mL) was added hydrazine hydrate (0.215 mL, 3.74 mmol). The reaction mixture was stirred at room temperature for 6 h. Precipitate was filtered off, the filtrate was evaporated and the residue was subjected to chromatography to give 59 (0.55 g, 77%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][CH:9]([OH:12])[C:10]#[CH:11].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[C:18]([Si:21]([O:12][CH:9]([CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[C:2]=1[Cl:1])[C:10]#[CH:11])([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:17]
Reactant: C#CC(O)CCc1sc2ccccc2c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(CCc1sc2ccccc2c1Cl)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
A solution of alcohol 18 (2.20 g, 8.78 mmol) in dichloromethane (15 mL) was treated with DMAP (215 mg, 1.8 mmol), TBSCl (1.59 g, 10.5 mmol), and triethylamine (1.8 mL, 13.2 mmol). The reaction was stirred for 24 h and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (2×50 mL) and the combined dichloromethane solution dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (4% ethyl acetate/hexane) gave 3.06 g (6.4 mmol, 73%) of the protected alcohol (19).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[F:18]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)c1c(F)c2cc(Br)ccc2n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a stirred solution of ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate (2.93 g, 10.39 mmol) in MeCN (52 mL) was added Selectfluor® (3.87 g, 10.92 mmol, 1.05 eq) at 0° C. in three portions with an interval of 10 min. The reaction was stirred at 0° C. for 30 min before it was allowed to warm to room temperature then stirred for an additional 30 min. The reaction was monitored by TLC analysis. Once the starting material was completely consumed, the reaction was quenched with sat. NaHCO3 and then extracted by CH2Cl2 (4×25 mL). The solvent was removed to give a crude product which was purified by flash column chromatography (0-10% EtOAc in hexanes) to afford the desired product (860 mg, 2.87 mmol) in 28% yield.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33]>>[C:1]1([CH:7]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccncc2)cc1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccncc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-(phenyl-4-pyridylmethoxy)piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-(phenyl-4-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH:8]([CH3:31])[CH2:9][NH:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[NH:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1)=[O:12]>C(Cl)Cl.CS(C)=O.O>[O:7]=[C:8]([CH3:31])[CH2:9][NH:10][C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19]2[NH:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)[N:23]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CC(O)CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a cooled solution (−78° C. to −60° C.) of oxalyl chloride (0.12 mmol) in CH2Cl2 (5 mL), DMSO (0.25 mmoL) was added dropwise. The mixture was stirred for 2 minutes, and then trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexane-carboxylic acid (2-hydroxy-propyl) amide (0.12 mmol) in 2 ml of CH2Cl2 was added. The mixture was stirred for 15 minutes at the same temperature following the addition of TEA (0.60 mmol). The mixture was stirred for another 5 minutes, warmed to room temperature and diluted with water. The organic layer was isolated, dried over Na2SO4, concentrated under vacuum, and purified with flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to give trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexane-carboxylic acid (2-oxo-propyl) amide.