Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccnc2cc(Br)ccc12
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Product: O=C(O)c1ccccc1Nc1ccnc2cc(Br)ccc12

Procedure:
7-Bromo-4-chloro-quinoline and 2-amino benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 2-(7-bromo-4-quinolylamino) benzoic acid.
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:13])=[CH:6][C:7]=1[CH3:12]
Reactant: CON(C)C(=O)c1ccc(Br)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1Br
Yield: 98.1 %

Procedure:
A solution of N-methoxy-N-methyl-4-bromo-3-methylbenzamide (D17) (12 g; 0.046 mol) in dry tetrahydrofuran (120 ml) under argon, at -78° C. was treated dropwise over 15 minutes with diisobutylaluminium hydride (1.5 m in toluene) (46 ml; 0.069 mol). After a further 15 minutes the reaction mixture was added to 5N HCl (100 ml) and extracted into diethyl ether. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a red oil (8.98 g, 97%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:14][CH2:13]1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2C#N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1C1CCN(CCCN)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[1-(3-tert-butoxycarbonylamino-propyl)piperidin-4-yl] benzonitrile (0.73 g, 2.1 mmol) in ethyl acetate (100 ml), cooled to 0° C. was added hydrogen chloride gas, bubbled vigorously for 5 minutes. The reaction mixture was stirred for 10 minutes at 0° C., purged with argon and concentrated. Flushing with ethyl acetate×2 and concentration gave 2-[1-(3-arninopropyl)-piperidin4-yl] benzonitrile hydrochloride; 1H NMR (DMSO) d 2.00 (m, 2H), 2.10 (m, 2H), 2.28 (m, 2H), 2.95 (m, 2H), 3.18 (m, 4H), 3.56 (bd, 2H, J=11.7 Hz), 7.47 (m, 2H), 7.75 (bt, 1H, J=8 Hz), 7.84 (bd, 1H, J=7.9 Hz), 8.14 (bs, 2H), 11.1 (bd, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]([O:9][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C

Procedure:
A Suspension of nicotinic acid (5.00 g, 40.6 mmol) in N,N-dimethylformaide (40 ml) was treated with sodium methoxide (2.19 g, 40.6 mmol). The resulting solution was treated with p-nitrobenzylbromide (8.77 g, 40.6 mmol) and heated at 50°, After heating 16 hrs the reaction was allowed to cool to ambient temperature and diluted with ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution and filtered. The organic fraction was separated and washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum to a solid.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([OH:19])=[C:14]([Cl:20])[CH:13]=1)=[O:11].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[C:10]([C:12]1[CH:13]=[C:14]([Cl:20])[C:15]([O:19][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:16]([Cl:18])[CH:17]=1)(=[O:11])[CH3:9]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)COc1c(Cl)cc(C(C)=O)cc1Cl
Reaction time: 0.5 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 1.32 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (10 ml) and, with stirring and cooling (ice-bath), a solution of 3,5-dichloro-4-hydroxyacetophenone (5.13 g) in dry DMF (15 ml) was added dropwise. Stirring was continued for 30 minutes when methyl bromoacetate (3.06 ml) was added dropwise and stirring was continued for a further 18 hours at ambient temperature. The reaction mixture was added to water, the mixture was extracted twice with ethyl acetate, the organic phases dried (MgSO4), filtered and then evaporated. The residue, after recrystallisation from hexane (250 ml), gave methyl 4-acetyl-2,6-dichlorophenoxyacetate, 4.25 g, as white crystals: NMR (d6DMSO) δ8.00 (2H, s), 4.80 (2H, s), 3.73 (3H, s), 2.59 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[NH:18]1[CH2:21][CH2:20][CH2:19]1>CO>[N:18]1([C:4]2[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: C1CNC1
Solvent: CO
Product: Clc1nc2c(c(N3CCC3)n1)CCC2c1ccccc1
Yield: 100.2 %

Procedure:
A solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg, 0.566 mmol) and excess azetidine (162 mg, 2.83 mmol) in methanol (1 mL) was stirred at rt for 30 min. The solvent was removed in vacuum to afford 4-(azetidin-1-yl)-2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (162 mg, 0.567 mmol, 100% yield). LC-MS (M+H)+=286.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][N:12](CC2C=CC=CC=2)[C@@H:11]([CH3:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][NH:12][C@@H:11]([CH3:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CN1

Procedure:
A 4.500 g (15.50 mmol) sample of (2S,4S)-4-t-butoxycarbonylamino-2-methyl-1-N-benzylpyrrolidine, from Example 2 above, was dissolved in 150 mL of methanol, 0.90 g of 10% Pd/C was added and the mixture shaken under 4 atm of hydrogen at room temperature for 13 hours. The mixture was concentrated, the catalyst was removed by filtration, and the solvent removed to afford 3.081 g of the title compound as a white solid. MS M/Z: 201 (M+H). NMR (CDCl3) δ: 1.15 (d, 3H, J=6 Hz), 1.44 (s, (1H), 1.54-1.63 (m, 2H), 1.75 (m, 1H), 2.64 (dd, 1H, J=5, J=12 Hz), 3.26 (m, 1H), 3.38 (dd, 1H, J=7, J=12 Hz), 4.12 (br, 1H), 4.63 (br, 1H). IR (KBr): 1685 cm-1.
Reaction SMILES: [Cl:1][CH:2]1[N:7](Cl)[CH:6]=[CH:5][N:4]=[CH:3]1.CN(C=O)C.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: ClC1C=NC=CN1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3,4-Dichloro-pyrazine (3 g, 20.1 mmol, 1.0 eq.), dry DMF (20 mL) and piperazine-1-carboxylic acid tert-butyl ester (7.3 g, 40 mmol, 2 eq). The reaction mixture was heated to 90° C. and allowed to stir for 4 hours. After allowing the reaction to return to room temperature water (100 mL) was added and the product extracted with DCM (2×200 mL). The organic layer was washed 1 N HCl (2×) and brine (2×) and dried over NaSO4. After removing the solvent the product was isolated as an orange oil (6 g, 80%).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:38])[N:25]([CH:35]4[CH2:37][CH2:36]4)[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=4[Cl:34])[CH2:21][C@@H:20]([NH2:39])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.Cl[C:42]([O:44][CH2:45][CH2:46][O:47][CH3:48])=[O:43]>CC#N>[CH3:48][O:47][CH2:46][CH2:45][O:44][C:42](=[O:43])[NH:39][C@@H:20]1[CH2:21][C@H:22]([C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:23][NH:18][CH2:19]1
Reactant: COCCOC(=O)Cl
Reactant: N[C@@H]1C[C@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: Cl
Solvent: CC#N
Product: COCCOC(=O)N[C@H]1CNC[C@@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)C1

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-piperidine-1 carboxylic acid 9H-fluoren-9-ylmethyl ester; hydrochloride and 2-methoxyethyl chloroformate. MS (LC-MS): 444.2/446.1 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.74 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[O:19]1[CH2:24][CH2:23][CH:22](OS(C)(=O)=O)[CH2:21][CH2:20]1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[O:12][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 52.6 %

Procedure:
Step B To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (13 mL) were added Cs2CO3 (2.9 g, 8.9 mmol) and methanesulfonic acid tetrahydropyran-4-yl ester (0.64 g, 3.6 mmol) sequentially. The reaction mixture was heated at 120° C. for 3 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (40-60% EtOAc in hexanes) to give 4-(3-methoxy-4-nitrophenoxy)tetrahydro-2H-pyran as a yellow oil (0.4 g, 53%).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C(O)C.O1CCCCC1.[Pd]>[O:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)[C:5]1[CH:26]=[CH:27][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)C1(CS(=O)(=O)c2ccc(Oc3ccc(Br)cc3)cc2)CCOCC1
Agent: [Pd]
Solvent: C1CCOCC1
Solvent: CCO
Product: O=C(O)C1(CS(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCOCC1
Yield: 100 %

Procedure:
A solution of 660 mg (1.45 mmol) of 4-[4-(4-bromophenoxy)phenylsulfonylmethyl]-tetrahydropyran-4 -carboxylic acid in 80% ethanol/tetrahydropyran (40 mL) was hydrogenated at atmospheric pressure for 14 hours using palladium on carbon catalyst, filtered over a celite pad washing with methylene chloride and concentrated in vacuo to afford 4-[4-phenoxyphenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid as a light orange solid (546 mg, 100%), which was taken directly into the next reaction without further purification: mp 162.5-165.3° C.; IR (KBr) 3431 (br), 1727 cm-1 ; 1HNMR (DMSO-d6) δ 1.67 (ddd, J=14.1, 10.0, 4.0 Hz, 2H), 1.95 (dm, J=14.1 Hz, 2H), 3.47 (mc, 2H), 3.65 (mc, 2H), 3.66 (s, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.27 (t, J=7.4 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.86 (d, J=7.9 Hz, 2H), 12.74 (s, 1H); 13C NMR (DMSO-d6) δ 32.88 (t), 42.26 (s), 61.75 (t), 63.26 (t), 117.64 (d), 120.11 (d), 125.03 (d), 130.04 (d), 130.39 (s), 134.69 (s), 154.69 (s), 161.53 (s), 174.39 (s); FABHRMS Calcd for C19H21SO6 (M+ +H): 377.1059. Found: 378.1064. Anal. Calcd. for C19H20SO6.0.75H2O: C, 58.52; H, 5.56. Found: C, 58.54; H, 5.19.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CC(C)=O>[CH2:12]([O:11][C:9]([NH:8][C@@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:24][CH:25]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
7.42 g (0.02 mol) of N-benzyloxycarbonyl-L-tyrosine tert-butyl ester were refluxed for 6 h together with 9.77 g(0.03 mol) of cesium carbonate and 3.9 g (0.02 mol) of ethyl 4-bromo-butyrate in about 60 ml of acetone. After cooling the reaction mixture, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water (1/1). After separation of the phases, the organic phase was washed two times each with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The oily crude product was purified by flash chromatography on silica gel (dichloromethane/acetonitrile 25/1). Yield: 9.4 g (97%) of viscous oil. Rf=0.36 (silica gel, dichloromethane/methanol 9911).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Li+].[Cl-].C[Sn](C)(C)[C:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:11]=[CH:10][C:9]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC=C([Sn](C)(C)C)CC1
Reactant: COC(=O)c1cc(I)ccc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
Methyl 2-fluoro-5-iodobenzoate (5.01 g, 17.9 mmol) was combined with LiCl (1.52 g, 35.7 mmol) and tert-butyl 4-(trimethylstannyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.28 g, 12.3 mmol) in 100 mL of DMF. After stirring for 20 min under a nitrogen atmosphere, Pd2dba3 (218 mg, 0.238 mmol) and P(2-furyl)3 (276 mg, 1.19 mmol) were added and the reaction mixture was warmed to 90° C. under a nitrogen atmosphere and stirred for 1 h 45 min. The reaction mixture was then stirred at rt overnight. Then the reaction temperature was brought again to 90° C. for 1 h. To the mixture was added saturated NaHCO3 solution and brine. The resulting aqueous mixture was then extracted three times with ether. The ethereal layers were combined and washed four times with water, dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 5-25% gradient of ethyl actetate/hexanes, over 2L volume) gave tert-butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate. 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J=7.0, 2.5 Hz, 1H), 7.53 (m, 1H), 7.13 (dd, J=10, 8.5 Hz, 1H), 6.07 (br s, 1H), 4.10 (br s, 2H), 3.96 (s, 3H), 3.66 (t, 6 Hz, 2H), 2.53 (br m, 2H), 1.52 (s, 9H). ESI-MS calc. for C18H22FNO4: 335; Found: 236 (M+Boc+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:34][C:35]1[C:43]2[C:42]([N:44]3[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][CH:36]=1>ClCCl>[CH3:1][N:2]1[C:6]([C:7]([NH:50][CH:47]2[CH2:46][CH2:45][N:44]([C:42]3[C:43]4[C:35]([CH3:34])=[CH:36][NH:37][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:49][CH2:48]2)=[O:9])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(=O)O
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4cncn4C)CC3)c12

Procedure:
To a mixture of 1-methyl-1H-imidazole-5-carboxylic acid (61.2 mg, 0.486 mmol, commercially available from e.g. Maybridge, Apollo or Butt Park), EDC (107 mg, 0.560 mmol), HOBt (86 mg, 0.560 mmol) and N,N-diisopropylethylamine (0.163 nit, 0.934 mmol) in Dichloromethane (DCM) (2 mL), prestirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.C1C(=O)N([I:18])C(=O)C1>CN(C)C=O>[I:18][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]nc(I)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (1000 mg, 7.40 mmol) in N,N-Dimethylformamide (DMF) (30 mL) stirred under nitrogen at room temperature was added NIS (1998 mg, 8.88 mmol). The reaction mixture was stirred at 80° C. for 5 h. The reaction was allowed to cool to room temperature. The mixture was concentrated, and NH4OH solution (20 ml) and EtOH (20 ml) were added. The precipitated white solid was filtered and dried to give 1.24 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. LC/MS (ES) m/z=261.9 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1.Cl.[OH-].[Na+]>C(O)C>[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: CC1=NCCc2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1NCCc2ccccc21
Yield: 93.9 %

Procedure:
1.76g of sodium borohydride(46 mM) was suspended in 80 ml of ethanol, and 6.48 g of the compound(44.6 mM) prepared in Step 2 above was added thereto. The resultant mixture was stirred at an ambient temperature for an hour and cooled to below 5° C., which was then acidified by adding dilute hydrochloric acid. After making the reaction solution alkaline by adding sodium hydroxide, it was extracted from ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 6.17 g of the title compound as oily substance.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:27]=[O:28])C>O>[CH2:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:27]=[O:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Cc2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2ccc(Cc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Freshly distilled POCl3 (0.122 ml) was added dropwise to cooled (ice bath) dry DMF (0.4 ml). The mixture was stirred 0.5 h at 0° C., then a solution of 5-benzylindole (0.24 g, 1.2 mmol) in DMF (0.14 ml) was added dropwise, during which time the temperature was maintained below 10° C. Once the solution was well mixed, the temperature was brought to 35° C. The syrup was stirred efficiently at this temperature for 1 h. At the end of the reaction period 0.4 g of crushed ice was added to the paste with careful stirring. The cherry-red solution was transferred with H2O (0.13 ml) to a flask containing 0.28 g of crushed ice. A solution NaOH (0.53 g, 13 mmol) in H2O (1.4 ml) was added dropwise; the suspension was heated to reflux, allowed to cool to room temperature, and was placed in a refrigerator overnight the precipitate was collected by filtration, washed well with H2O and air-dried to provide 0.15 g (56%) of 5-benzyl-3-formylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(C1C=C(C=C(C)C=1O)[C:15]#[N:16])C>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9])[C:15]#[N:16]
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: Cc1cccc(Cl)c1O
Product: Cc1cc(C#N)cc(Cl)c1O

Procedure:
The title compound is prepared from commercially available 2-chloro-6-methyl-phenol in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: tR=0.85 min. 1H NMR (CDCl3): δ2.33 (s, 3H), 6.10 (s, 1H), 7.38 (s, 1H), 7.53 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH2:1]([Li])[CH3:2].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[CH2:26][CH3:27])=[CH:12][CH:11]=1)=[O:9].[Cl-].[NH4+]>O1CCCC1>[CH2:26]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[O:5][CH3:4])([OH:9])[CH2:1][CH3:2])=[CH:15][CH:14]=1)[CH3:27]
Reactant: [Li]CC
Reactant: CCC1CCCCN1CCCOc1ccc(C(=O)c2ccccc2OC)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1CCCCN1CCCOc1ccc(C(O)(CC)c2ccccc2OC)cc1
Temperature: -15 °C

Procedure:
To 125 ml. of a 0.8 molar ethereal ethyl lithium solution a solution of 15.3 g. of 2-methoxy-4'-[3-(2-ethyl-piperid-1-yl)-propoxy]-benzophenone in 50 ml. of tetrahydrofuran is added dropwise, in argon atmosphere, with stirring at -15° C. The reaction mixture is stirred at room temperature for another two hours, whereupon it is decomposed with a saturated aqueous ammonium chloride solution under cooling. The aqueous phase is extracted with ether. The combined organic phases are washed with a saturated aqueous sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent is distilled off under reduced pressure, and the residue is fractionated. 7.6 g. of the title compound are obtained. The physical characteristics of the product are identical with those given in Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH2:21]([NH2:23])[CH3:22]>CN(C)C=O.O>[Cl:8][C:7]1[C:2]([NH:23][CH2:21][CH3:22])=[N:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reactant: CCN
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reaction time: 6 h

Procedure:
2,3-Dichloro-5,6-diphenylpyrazine (2.00 g, 0.0066 moles), is suspended in dimethylformamide (DMF) (12 ml) and treated with a solution of ethylamine (70% in water) (3.5 ml) in DMF (6ml) and the mixture is warmed at 40°-45°C for 30 minutes then allowed to stand at room temperature for 6 hours. The solution is diluted with water (80 ml) and after standing overnight the solid is filtered off, washed with water and dissolved in hot ethyl alcohol, filtered, concentrated and cooled to yield 1.19 g of greenish-yellow solid. m.p. 115°-122°. This material is recrystallized from an ethyl alcohol-hexane mixture, yield 0.84 g, m.p. 121°-125°. Identity of the product is confirmed by infrared, nuclear magnetic resonance and mass spectra.