Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH:21]1(N)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[CH:21]1([NH:20][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:16]=3[N:17]=[CH:18][N:19]=2)[C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NC1CCCCC1
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 6-chloroadenosine (2.58 g) and cyclohexylamine (5 g) in ethanol (20 ml) was heated at reflux for 6 hours then cooled to room temperature. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with water (50 ml) and ethyl acetate (300 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (1×30 ml), dried over sodium sulfate, concentrated in vacuo and dried under vacuum to provide N6-cyclohexyladenosine as a white solid (2.600 g). N6-Cyclohexyladenosine (2.6 g) was diluted with acetone (30 ml) and to the resultant solution was added 2,2-dimethoxypropane (12 ml), followed by D-camphorsulphonic acid (3.01 g) and the mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with ethyl acetate (150 ml), then neutralized to pH 8.0 using saturated aqueous NaHCO3. The organic layer was separated, dried over sodium sulfate, concentrated in vacuo. The residue was purified twice on the silica gel column using MeOH—CH2Cl2 (4:96) as an eluent to provide 2′,3′-isopropylidene-N6-cyclohexyladenosine (3.16 g). 1H NMR (CDCl3): δ 1.23-1.47 (m, 9H), 1.38 (s, 3H), 1.64 (s, 3H), 1.79-1.81 (m, 1H), 2.04-2.06 (m, 1H), 3.80 (d, J=12 Hz, 1H), 3.96 (d, J=12 Hz, 1H), 4.53 (s, 1H), 5.09-5.16 (m, 2H), 5.80-5.92 (m, 2H), 7.79 (s, 1H), 8.24 (s, 1H), 8.22-8.38 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[CH2:24](OC(OCC)OCC)C>[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(#N)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[N:4]=[C:3]([C:22]#[N:23])[C:2]3[N:1]=[CH:24][NH:8][C:7]=3[CH:6]=2)=[CH:10][C:11]=1[C:18]([F:21])([F:19])[F:20])[CH3:17]
Reactant: CCOc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCOc1ccc(-c2cc3[nH]cnc3c(C#N)n2)cc1C(F)(F)F
Yield: 57.1 %

Procedure:
A stirred suspension of 3,4-diamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (4.4 g, 13.7 mmol), ytterbium triflate (173 mg, 2 mol %), triethylorthoformate (6.08 g, 41.1 mmol) and acetonitrile (50 ml) was heated to reflux for 30 minutes. The solid precipitate was collected by filtration and washed sparingly with acetonitrile to afford 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (2.6 g). 1H NMR (DMSO): δ 8.67 (s, 1H), 8.47 (s, 1H), 8.36 (m, 2H), 7,49 (d, 1H), 4.26 (q, 2H), 1.38 (t, 3H). MS m/z 333.3(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1F.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:14][CH3:13]
Reactant: C[O-]
Reactant: CS(=O)(=O)c1ccc(Br)c(F)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(S(C)(=O)=O)ccc1Br
Yield: 53 %

Procedure:
To a solution of 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (Preparation 14, 1.5 g, 5.93 mmol) in MeOH (12 mL) was added sodium methoxide (480 mg, 8.89 mmol) and the reaction mixture was irradiated at 100° C. in the microwave for 1.5 hours. After this time the reaction was quenched with water (50 mL) and the product was extract with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptane to afford the title compound as colourless solid in 53% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:10]1)(=[O:8])=[O:7].[CH3:36]C(S(Cl)(=O)=O)CC>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][NH:29][S:30]([CH:33]([CH2:35][CH3:36])[CH3:34])(=[O:31])=[O:32])[CH2:10]1)(=[O:7])=[O:8]
Reactant: CCC(C)S(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Product: CCC(C)S(=O)(=O)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1

Procedure:
According to the procedure for Example 237, the reaction of 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (Example 237, Step 2) and butane-2-sulfonyl chloride (Sigma-Aldrich, St. Louis, Mo.) gave N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-butanesulfonamide as a mixture of 4 compounds.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>[Pd].C(O)C>[C:9]1([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C=C(Br)CCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1C=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
A microwave vial was charged with a stir bar, 3-bromocyclohex-2-enone (65 mg, 1 equiv., 0.37 mmol), phenyl boronic acid (55 mg, 1.2 equiv., 0.45 mmol) and ethanol (4 mL). To the solution was added 1M K2CO3 (1.2 equiv., 0.45 mmol) followed by the addition of the polymer supported palladium FC 1001 (27 mg, 3 mol % Pd) catalyst. The reaction was subjected to the following microwave conditions: Power 250 W, Temperature 110° C., ramp time 1:00 min, time holds 5 min, Power Max on (continuous air cooling). The reaction was then cooled to room temperature and filtered through a plug of celite eluding with ethyl acetate. The solvent was evaporated on a rotary evaporator. The residue was diluted in methylene chloride and washed with brine. The organic layers were dried over MgSO4 and the residue was purified by automated silica gel chromatography using gradient elution (0 to 20% ethyl acetate/hexanes) affording the desired product as a white solid (48 mg, 75% yield). 1H NMR (300 MHz, CDCl3): δ 7.50-7.53 (m, 2H), 7.36-7.41 (m, 3H), 6.40 (t, J=1.4 Hz, 1H), 2.76 (td, J=6.9, 1.2 Hz, 2H), 2.48 (t, J=6.9 Hz, 2H), 2.14 (quintet, J=6.9 Hz, 2H). 13C (75 MHz, CDCl3): 199.6, 159.6, 138.6, 129.8, 128.6, 125.9, 125.3, 37.3, 28.1, 22.9. LCMS (ESI): mass calcd for (C12H12O) m/z 172.09; measured [M+H]+: m/z 173.17.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:29][C:30](=[NH:35])[CH2:31][CH2:32][O:33][CH3:34]>>[CH3:34][O:33][CH2:32][CH2:31][C:30]1[N:35]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:29]=1
Reactant: COCCC(=N)NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 242 mg (1.640 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 350 mg (46% of theory)
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][O-:14].[Na+]>CO.CCOC(C)=O>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:3]([CH2:2][O:14][CH3:13])[C:4]=1[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cc(Cl)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
To a suspension of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.04 mmol) (A.2.2.1.) in 2.5 mL MeOH was added a solution of NaOMe (1.27 mmol, 0.5M in MeOH). The reaction mixture was heated to 50° C. for 1 h. The mixture was conc. in vacuo, redissolved in EtOAc and it was then washed twice with an aq. soln. of KHSO4, twice with a sat. aq. NaHCO3 soln. and once with brine. The org. layer was dried over MgSO4 and conc. in vacuo to give the desired product as orange oil.
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+:17].P([O-])([O-])(O)=O.[NH4+].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:17])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: O=P([O-])([O-])O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
Ammonium picrate (0.92 g, 3.7 mmol) and diammonium hydrogen phosphate (0.99 g, 7.5 mmol) are suspended in dry sulfolane (3 ml) and stirred in a Teflon® capped glass pressure tube (8 ml) for 2 hr with the application of heat, which raises the temperature of the reaction from 25° C. to 177° C. The reaction is continued an additional 5 hr at 177° C. and cooled to ambient temperature. Water (30 ml) is added to the slurry and the product is collected and washed with water. Vacuum drying yields 0.74 g picramide (87%) (Table 1, entry 2).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:25](OC)[C:26](=C=O)[CH:27]=[CH:28][CH:29]=2)[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:34]([O:36][CH3:37])=[O:35])[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(C3=CC=CC(=C=O)C3OC)cc(C(=O)OC)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1
Yield: 153.9 %

Procedure:
65.5 mg (0.126 mmol) of methyl 6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonylphenyl)-4-quinolinecarboxylate obtained in Example 5 were dissolved in a mixed solvent of 2 ml of tetrahydrofuran and 2 ml of methanol and the mixture was stirred. After adding 5.24 mg (0.139 mmol) of sodium borohydride, the reaction mixture was allowed to react at room temperature for one hour. Then, the reaction mixture was concentrated under reduced pressure and dichloromethane was added to the residue followed by washing with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 50.6 mg of methyl 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonylphenyl)-4-quinolinecarboxylate.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:9][C:10]1[C:15](Br)=[N:14][CH:13]=[CH:12][N:11]=1>C1COCC1>[Br:9][C:10]1[N:11]=[CH:12][C:13]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[N:14][CH:15]=1
Reactant: Brc1nccnc1Br
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnc(N2CCOCC2)cn1
Reaction time: 0.25 h

Procedure:
To sodium hydride (0.20 g) taken in THF (15 ml), morpholine (0.735 ml) was added under nitrogen, at 0° C. The reaction mixture stirred for about 15 minutes, then 2,3-dibromopyrazine (2 g) dissolved in dry THF (15 ml) was added. The reaction mixture was allowed to stir at reflux conditions for overnight. The reaction mixture was quenched with water (5 ml), and volatiles were removed under vacuum. The resulting crude mass was purified by column chromatography to afford pure 4-(5-bromopyrazin-2-yl)morpholine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[C:22]([N+:33]#[C-:34])[S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:4]=1.Cl[CH2:36][O:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:22]([N+:33]#[C-:34])([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:36][O:37][CH3:38])[CH:4]=1
Reactant: COCCl
Reactant: [C-]#[N+]C(=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Product: [C-]#[N+]C(COC)(C1=CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared according to the process described in Example 8a, starting with 3-methoxy-17-(isocyano-p-methylphenylsulfonylmethylene)-androsta-3,5-diene (477 mg, 1 mmol) and chloromethylmethylether (0.2 ml). Yield: 385 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.[CH2:17]([O:19][CH2:20][CH2:21]Cl)[CH3:18]>>[CH2:17]([O:19][CH2:20][CH2:21][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH3:18]
Reactant: CCOCCCl
Reactant: CN1CCC(c2nc3cccnc3[nH]2)CC1
Product: CCOCCn1c(C2CCN(C)CC2)nc2cccnc21

Procedure:
Operation is carried out similarly to the above description with the difference that 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine is reacted with 2-ethoxyethyl chloride to obtain 3-(2-ethoxyethyl)-2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine which is isolated as hemitrifumarate melting at 157°-158° C. (ethyl alcohol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][OH:4].[OH-].[K+].[C:17](Cl)(Cl)=[O:18]>C1(C)C=CC=CC=1.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:17](=[O:18])[NH:1]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N[C@@H](Cc2ccc([N+](=O)[O-])cc2)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from step (b) (4.9 g) was suspended in toluene, the suspension cooled to 0° C. and a solution of potassium hydroxide (7.0 g) in water (56 ml) added dropwise. A solution of phosgene (62.5 ml of a 12% w/v solution in toluene) was added dropwise to the resulting solution over 30 minutes and stirring continued for 1 hour. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried and evaporated in vacuo to give a yellow oil. Crystallisation from ethyl acetate gave the desired product as pale yellow crystals (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[N:8]=[C:7]([C:23]([OH:25])=O)[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:18]([O:17][P:15]([C:12]([C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([C:23]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:25])=[N:8]2)=[CH:3][C:2]=1[Br:1])([F:13])[F:14])(=[O:16])[O:20][CH2:21][CH3:22])[CH3:19]
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)Nc3ccccc3)ccc2cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product of step 5 (109 mg) in 5 mL CH2Cl2 was added EDCI (96 mg), aniline (0.1 mL) and Hunig's base (0.1 mL). The solution was stirred at ambient temperature for 3 hours and after concentration and flash chromatography on silica with a gradient of 10-25% EtOAc/toluene the amide was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:9]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1cc(Br)cs1
Reactant: C#CCCCCCC
Product: CCCCCCC#Cc1csc(C=O)c1
Yield: 89 %

Procedure:
Reaction of 4-bromo-2-thiophenecarboxaldehyde (3.40 g 2 mmole, prepared by the methods described by D. Chadwick et al, J.C.S. Per 1 1766, 1973), with 1-octyne (4.40 g, 4 mmole) as described in Example 20 gave the title compound as a yellow oil (89.0%); mp 2° C.; νmax 3100, 2260, 1685, 1160, 855, 655, 622; δH(CDCl3) 0.88(3H, t, J=6 Hz), 1.3(8H, m), 2.33(2H, t, J=6 Hz), 7.7(2H, s), 9.9 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:13])(O)[C:10]#[N:11]>C(OCC)(=O)C>[CH3:8][C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[C:10]#[N:11]
Reactant: Nc1ccccc1
Reactant: CC(C)(O)C#N
Solvent: CCOC(C)=O
Product: CC(C)(C#N)Nc1ccccc1
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of aminobenzene (0.931 g, 10 mmol) and acetone cyanohydrin (2 ml) was heated to reflux and stirred for 20 h. After being cold to room temperature, the reaction mixture was poured into ethyl acetate (40 ml) and washed with cold water (2×30 ml). The organic layer was dried over MgSO4, concentrated under vacuum to dryness to yield 2-methyl-2-phenylaminopropanenitrile, 6a (1.51g, 9.4 mmol, 94%) as slurry brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1)=[O:4].O.O.O.[O-:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: [O-]c1ccccc1
Reactant: COC(=O)c1cnc(S(C)(=O)=O)nc1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(Oc2ccccc2)nc1
Temperature: 100 °C
Yield: 65.7 %

Procedure:
To a solution of 2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester (0.8 g, 3.7 mmol) in NMP (3 mL) is added sodium phenoxide trihydrate (0.68 g, 4 mmol). The mixture is heated at 100° C. in Biotage Microwave for 60 sec. The reaction is poured into water and the precipitate is collated by filtration and dried to afford 2-phenoxy-pyrimidine-5-carboxylic acid methyl ester (0.56 g, 66%) as a solid. MS: 231 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.75 (s, 3H), 7.19-7.33 (m, 3H), 7.46 (t, 2H) 9.10 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([N:21]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH2:4][CH2:3]1.[ClH:35].O1CCOCC1>ClCCl>[ClH:35].[ClH:35].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([N:21]([CH:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)O)CC1
Reaction time: 1.5 h

Procedure:
tert-Butyl 4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoate (1.18 g, 2.435 mmol) was dissolved in dry dichloromethane (3 mL) under nitrogen atmosphere. A 4 M solution of HCl in dioxane (9.1 mL, 36.4 mmol, 15 eq) was then added dropwise and the mixture was stirred for 1.5 hours. A sticky solid was formed. 5 more equivalents of HCl were added and the mixture was stirred for 2 more hours. The solid was filtered, washed with DCM (10 mL) and diethyl ether (10 mL) and dried under vacuum at 60° C. for 2 hours. 1.06 g of title compound were obtained as a beige powder (87% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[N:13]1([CH2:11][C:9]2[O:10][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:7][CH:8]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: CC(=O)OCc1ccc(C=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)OCc1ccc(CN2CCOCC2)o1
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, to a solution of 2.0 g of 5-acetoxymethyl-2-furanaldehyde and 1.1 mL of morpholine in 35 mL of 1,2-dichloroethane was added 4.0 g of sodium triacetoxy borohydride at room temperature, and stirred at this temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified and separated by silica gel column chromatography, to afford 2.3 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:16]([N:23]1[CH2:27][CH2:26][C@@H:25](O)[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:25]1[CH2:26][CH2:27][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CCOC(=O)c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a cold (0° C.) mixture of ethyl-5-hydroxyindole-2-carboxylate (purchased at Biosynth, H-6350, 20.5 g, 1.0 eq.), (R)-1-benzyl-3-pyrrolidinol (23 g, 1.3 eq.) and tri-n-butylphosphine (58 mL, 2.0 eq.) was slowly added 1,1′-(azodicarbonyl)dipiperidine (50.4 g, 2.0 eq.) in several portions. The reaction mixture was stirred at room temperature overnight and then filtered off. The filtrate was concentrated in vacuo and diethylether was added. The precipitate was filtered off and the filtrate was concentrated in vacuo and purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 18 mg (49%) of the desired product as light yellow foam. MS (m/e): 365.5 (MH+, 100%).