Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)(=[O:14])=[O:13].Cl>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)(=[O:14])=[O:13]
Reactant: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl 4-{[2-methyl-5-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 23) (2.1 g, 5.14 mmol) in 1,4-dioxane (50 mL) was treated by HCl 4M in dioxane (6.43 mL, 25.7 mmol). The reaction mixture was stirred overnight at room temperature. LCMS showed a mixture of starting material and product so 8 ml of HCl 4M in dioxane were added. LCMS after 2 h showed still some starting material so 5 ml of HCl 4M in dioxane were added. LCMS after 2 h showed traces of starting material.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[NH:10]1[C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[C:13]=2[CH:12]=[CH:11]1>C1COCC1>[I:1][C:12]1[C:13]2[C:14]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])=[N:15][CH:16]=[CH:17][C:18]=2[NH:10][CH:11]=1
Reactant: CCOC(=O)Nc1nccc2[nH]ccc12
Reactant: NC(=O)CCC(=O)NI
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nccc2[nH]cc(I)c12
Reaction time: 0.25 h
Yield: 72 %

Procedure:
N-Iodosuccinamide (0.030 g, 0.13 mmol, 1.0 eq) was added to a solution of ethyl 1H-pyrrolo[3,2-c]pyridin4-ylcarbamate (0.027 g, 0.13 mmol, 1.0 eq) in THF (1 mL) at room temperature and the reaction mixture was stirred for 15 minutes. The reaction mixture was quenched with 10% NaHSO3 solution and extracted with 10/1 CHCl3/MeOH. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting 0-5% CHCl3/MeOH) to afford the product (0.031 g, 72%) as a solid. 1H NMR (CD3OD) δ 7.87 (d, 1H, J=5.9 Hz), 7.38 (s, 1H), 7.25 ((d, 1H, J=5.9 Hz), 4.14 (q, 2H, J=7.1 Hz), 1.12 (t, 3H, J=7.1 Hz); MS(ESI+) m/z 332 (M+H)+. Calculated: 331.9896, found: 331.9884.
Reaction SMILES: C([N+]([O-])=O)(C)(C)C.[N+:8]1([O-:22])[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[N:11]=[C:10](N)[N:9]=1.C(I)[I:24]>C1COCC1.[Cu]I>[I:24][C:10]1[N:9]=[N+:8]([O-:22])[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[N:11]=1
Reactant: ICI
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Agent: [Cu]I
Agent: CC(C)(C)[N+](=O)[O-]
Solvent: C1CCOC1
Product: [O-][n+]1nc(I)nc2cc3c(cc21)CCO3
Temperature: 20 °C
Yield: 48.6 %

Procedure:
tert-BuNO2 (90%, 3.8 mL, 28.8 mmol) was added to a stirred solution of 1-oxide 204 (2.0 g, 9.8 mmol), CH2I2 (3.8 mL, 46.7 mmol) and CuI (1.87 g, 9.8 mmol) in THF (40 mL), and the mixture was stirred at reflux temperature for 7 h. The mixture was cooled to 20° C., the solvent was evaporated and the residue purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give iodide 213 (1.50 g, 49%) as a pale yellow solid: mp 192-194° C.; 1H NMR δ 8.19 (t, J=1.6 Hz, 1H, H-9), 7.10 (s, 1H, H-5), 4.83 (t, J=8.4 Hz, 2H, H-7), 3.44 (dt, J=8.4, 1.6 Hz, 2H, H-8); 13C NMR δ 167.0, 150.4, 136.2, 123.3, 116.4, 105.8, 103.7, 73.4, 29.0; HRMS calcd for C9H6IN3O2(M+) m/z 314.9505, found 314.9501.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[CH:25]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: OB(O)c1cccc(-c2cccs2)c1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(-c3cccs3)c2)cc1
Yield: 63.4 %

Procedure:
The title compound (243 mg, 77.6%, yellow foam) was prepared from [2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (310 mg, 0.922 mmol, prepared in example 1), 3-(2-thienyl)benzeneboronic acid (145 mg, 1.13 mmol), dichlorobis(triphenylphosphine)palladium(II) (26 mg, 0.037 mmol), 2 M sodium carbonate (335 mg in 1.6 mL water), and 1,2-dimethoxyethane (6 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]([N:13]1[CH2:17][CH2:16][CH:15]2[N:18]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:19][CH:20]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH:14]12)=[O:12])[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH2:9][CH3:10])[C:11]([N:13]1[CH2:17][CH2:16][CH:15]2[N:18]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:19][CH:20]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH:14]12)=[O:12]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
To a solution containing 64 (270 mg, 0.53 mmol) in DCM (3 mL) was added TFA (2 mL) at 0° C. After 90 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 150 mg (69%) of 65 which was used without further purification. Mass spectrum, m/z [409.2] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([NH:20][CH2:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: NCC1CCCCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(NCC2CCCCC2)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 2.62 g; 12.7 mmol) in anhydrous THF (95 mL) was treated with a solution of cyclohexanemethylamine (Aldrich, 1.68 mL; 12.66 mmol) and triethylamine (1.93 mL; 13.92 mmol) in THF (35 mL). The reaction mixture was stirred during 30 min. Water (50 mL) was poured into the reaction mixture, which was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:27]5[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][C:22]=5[C:21]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=5)=[N:20]4)[CH2:12][CH2:11]3)=[C:8]([C:42]([OH:44])=O)[S:7][C:6]=2[CH:45]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:79][CH2:80][CH2:81][N:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>CN(C=O)C>[N:82]1([CH2:81][CH2:80][NH:79][C:42]([C:8]2[S:7][C:6]3[CH:45]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:9]=2[CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:27]4[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:23][C:22]=4[C:21]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=4)=[N:20]3)[CH2:14][CH2:15]2)=[O:44])[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)NCCN4CCOCC4)sc4cc(F)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min before the addition of 20 μL (0.15 mmol) of 4-(2-aminoethyl)morpholine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica, 5-10% of (2 N NH3 in MeOH)/CH2Cl2) afforded 15 mg (65%) of a white solid. MS (electrospray), exact mass calculated for C37H44F4N6O4S2: 776.28; m/z found, 777.3 [M+H]+. 1H NMR (CDCl3, 400 MHz): 8.07 (brs, 1H), 7.73 and 7.66 (A and B of AB quartet, J=8.41 Hz, 4H), 7.50 (dd, J=8.41, 2.35 Hz, 1H), 7.14 (dt, J=8.61, 2.54 Hz, 1H), 6.64 (t, J=4.70 Hz, 1H), 4.56 (s, 2H), 4.16 (t, J=6.85 Hz, 2H), 3.80-3.67 (m, 7H), 3.53 (q, J=5.48 Hz, 2H), 3.03 (br m, 2H), 2.98 (t, J=5.67 Hz, 2H), 2.90 (s, 3H), 2.60 (t, J=5.87 Hz, 2H), 2.38 (br m, 4H), 2.12 (br m, 4H), 1.86-1.73 (br m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].Br[CH2:13][C:14]#[C:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][C:14]#[C:15][CH3:16])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (271 mg) and 1-bromo-2-butine (283 mg) in DMF (5 ml) was treated with potassium carbonate (367 mg) and heated to 100° C. for 16 h. the mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue was purified by chromatography using heptane/ethyl acetate (gradient from 0-80% ethyl acetate) to give the title product (266 mg) as a pale yellow solid. MS: m/z=206.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH2:20][CH:21]=[CH2:22]>CCOCC>[CH2:1]([O:8][C@H:9]([C@@H:10]([OH:11])[CH2:22][CH2:21][CH:20]=[CH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@H](Cc1ccccc1)OCc1ccccc1
Reactant: C=CCC[Mg]Br
Solvent: CCOCC
Product: C=CCC[C@H](O)[C@H](Cc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
The latter aldehyde was dissolved in Et2O (20 mL). Under anhydrous conditions, the solution of the aldehyde was added dropwise over 15 min to a stirred solution of 3-butenyl magnesium bromide at -78°. The latter solution had been prepared by diluting 71 mL of a 0.64M solution of the Grignard reagent in Et2O with 155 mL of Et2O. After 1 h, the reaction mixture was diluted with Et2O (100 mL). The resulting mixture was washed with a saturated aqueous solution of NH4Cl and then with brine. The organic phase was dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography (SiO2, eluent: hexane-EtOAc, 9:1) to give (2S,3S)-2-benzyloxy-1-phenyl-6-hepten-3-ol (4.82 g), 1H NMR (CDCl3) δ 7.25 (m, 10H), 5.75 (m,1H), 4.95 (m,2H), 4.40 (dd,2H), 3.50 (m, 2H), 2.90 (m,2H), 2.10 (m,3H), 1.60 (m,2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:11]([CH3:25])([CH3:24])[CH2:10]2)=[O:4].ON1C2C=CC=CC=2N=N1.[CH3:36][N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]=C=NCC.Cl.CN1CCOCC1.CN1CCC(N)C1>ClCCl>[CH3:25][C:11]1([CH3:24])[CH2:10][C:9]2[C:14](=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:41][CH:40]2[CH2:39][CH2:38][N:37]([CH3:36])[CH2:46]2)[CH:16]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1cccc2c1NC(c1cccc(C(=O)O)c1)C(C)(C)C2
Agent: CN1CCC(N)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cccc2c1NC(c1cccc(C(=O)NC3CCN(C)C3)c1)C(C)(C)C2
Reaction time: 1 h

Procedure:
To a suspension of 3-(8-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (63 mg, 0.19 mmol) in dichloromethane (5.0 mL) was added N-hydroxybenzotriazole (37.6 mg, 0.28 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (106.7 mg, 0.56 mmol), followed by 4-methylmorpholine (56.3 mg, 0.56 mmol) and the resultant mixture was stirred at room temperature for 1 h., then 1-methylpyrrolidin-3-amine (27.9 mg, 0.28 mmol) was added to the flask and the reaction mixture was stirred for an additional 1 h. LC-MS showed the reaction was complete. The reaction was quenched with water and separated. The aqueous layer was extracted with dichloromethane (twice) and the combined organic layers were washed with 5% sodium hydroxide aqueous solution (twice) and water (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 76 mg of methyl 3,3-dimethyl-2-(3-(1-methylpyrrolidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate as a white solid, which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][N:6]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[C:7]=2[CH:8]=[CH:9][N:10]=1
Reactant: Clc1nccc2[nH]ccc12
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2ccc3c(Cl)nccc32)cc1
Yield: 48.8 %

Procedure:
To 4-Chloro-5-azaindole (120 mg, 079 mmol) in 5 ml DMF was added 4-Fluorobenzylbromide (0.120 ml, 0.95 mmol) then add NaH (32 mg, 0.79 mmol) and stir at room temperature overnight. Work up reaction by adding water and EtOAc then extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 100 mg (50%) of product.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][C@@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[OH:26])[CH2:19]3)[C:6]=2[CH:5]=1.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:33][N:21]1[CH2:22][CH2:23][N:18]([C:7]2[C:6]3[CH:5]=[C:4]([CH3:3])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:19][C@@H:20]1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](C[C@H](O)c2ccccc2)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](C[C@H](O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
Add formaldehyde (33 μL, 0.42 mmol, 37% in water) to a solution of (S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol (160 mg, 0.38 mmol) in methylene chloride (6 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (121 mg, 0.57 mmol) and stir 2 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–5%) as the eluent to give 70 mg (42%) of the title compound: mass spectrum (ion spray): m/z=433 (M+1), 431 (M−1). HR-MS calculated for C25H29N4OS: 433.2062. Found 433.2061. 1H NMR (DMSO-d6): δ 7.60 (s, 1H), 7.36–7.17 (m, 5H), 6.88–6.75 (m, 3H), 6.68 (br d, 1H), 6.35 (s, 1H), 5.34 (br d, 1H), 4.60–4.50 (m, 1H), 3.85 (br d, 1H), 3.70 (br d, 1H), 3.04–2.92 (m, 1H), 2.85–2.66 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.20–2.10 (m, 1H) 2.08–1.98 (m, 1H), 1.97–1.85 (m, 1H), 1.66–1.52 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:19]1([S:25][CH2:26][CH2:27]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[ClH:29]>O.CN(C)C=O>[ClH:29].[C:19]1([S:25][CH2:26][CH2:27][N:16]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCSc1ccccc1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCN2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccncc2)nc2n1CCN2CCSc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.2 g (0.93 mmol) of 7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in ml of anhydrous N,N-dimethylformamide was added 48.5 mg (1.21 mmol) of sodium hydride (60% suspension in mineral oil) and the resulting mixture was heated at 70° C. during 30 min. There was added 0.32 g (1.49 mmol) of 2-bromoethyl phenyl sulfide and heating was continued at 130° C. during 1 h. Water was added to the cooled mixture and the resulting solution extracted with ethyl acetate. The combined extracts were washed with water and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 98/2/0.2 to obtain pure compound as free base. The compound was converted to the hydrochloride salt by addition of hydrochloric acid to an isopropylic solution of the free base. There is obtained 0.11 g of product as a yellow solid.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[N:19]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[NH:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:22]2[CH:23]=[CH:18][N:19]=[C:20]([NH:24][CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[N:21]=2)=[CH:7]1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cccnc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (prepared by TBDMS protection of 1H-pyrrolo[2,3-b]pyridine) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:45])[CH2:14][CH2:15][N:16]([C:23]([C:25]1[CH:44]=[CH:43][C:28]2[N:29]([CH3:42])[C:30]([CH2:32][NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C)(C)C.C(=O)([O-])[O-].[NH4+:51].[NH4+]>Cl.C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:14][CH2:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]([C:25]1[CH:44]=[CH:43][C:28]2[N:29]([CH3:42])[C:30]([CH2:32][NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40](=[NH:41])[NH2:51])=[CH:36][CH:35]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])=[O:45]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NCCCCNC(=O)OC(C)(C)C)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)NCCCCN)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
The product of 1f (4.81 mmol) was dissolved in a saturated solution of HCl in ethanol (250 mL), the mixture stirred at room temperature over night and then evaporated to dryness at 30° C. The remaining raw material was dissolved in 200 mL dry ethanol, then ammonium carbonate (48.1 mmol) was added and the mixture stirred at room temperature over night. After evaporation of the solvent the remaining raw material was triturated with ca. 5 mL ethanol, the undissolved material separated by filtration and the solvent evaporated at 30° C. The product was then dissolved in 30 mL water, the solution stirred with ca.2g charcoal, filtered and evaporated to dryness.
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C@:5]([NH2:18])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:6][CH2:7][CH3:8].[CH3:20][NH:21][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=S>>[C:27]([O:26][C:25](=[O:31])[NH:24][C:22]1[N:21]([CH3:20])[C:3](=[O:19])[CH2:4][C@:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)([CH2:6][CH2:7][CH3:8])[N:18]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCC[C@](N)(CC(=O)OC)c1cccc([N+](=O)[O-])c1
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CCC[C@@]1(c2cccc([N+](=O)[O-])c2)CC(=O)N(C)C(NC(=O)OC(C)(C)C)=N1

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-hexanoic acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-1-methyl-4-(3-nitro-phenyl)-6-oxo-4-propyl-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as an amorphous solid. MS (ESI): m/z=389.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][N:5]2[C:17](=[O:20])[NH:18][N:19]=[C:4]2[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:23][N:18]1[C:17](=[O:20])[N:5]2[N:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[C:2]([CH3:1])=[CH:3][C:4]2=[N:19]1
Reactant: Cc1cc2n[nH]c(=O)n2nc1-c1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nn(C)c(=O)n2nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A suspension of 3.0 g. of 7-methyl-6-(m-nitropheyl)-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one in 30 ml. of dry dimethylformamide is stirred for 10 minutes. A 0.54 g. portion of a 50% oil suspension of sodium hydride is added and the mixture is stirred for 1/2 hour with cooling. A 0.75 ml. portion of methyl iodide is added, the mixture is stirred for one hour and then filtered. The solid is washed with water and dried, giving 2.12 g. of the desired product as a yellow solid, m.p. 250°-253° C.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH:15][C:16]1[C:24]([CH:25]=[O:26])=[CH:23][C:19]2[CH2:20][CH2:21][O:22][C:18]=2[C:17]=1[O:27][CH3:28]>O1CCOCC1>[OH:15][C:16]1[C:24]([CH:25]=[O:26])=[CH:23][C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]=1[O:27][CH3:28]
Reactant: COc1c(O)c(C=O)cc2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1c(O)c(C=O)cc2ccoc12

Procedure:
A solution of 817 mg. (3.6 mmole) of DDQ in 10 ml. of dioxane was added to 582 mg. (3 mmole) of 2,3-dihydro-6-hydroxy-7-methoxy-5-benzofurancarboxaldehyde in 15 ml. of dioxane and the resulting mixture was heated under reflux for 7 hours, cooled and the formed solid removed by filtration. The precipitate was thoroughly washed first with benzene, then with CHCl3. The washings were combined with the initial filtrate and the total concentrated in vacuo to a residue which was chromatographed first on a 20 ml. dry silica gel column (E. Merck 7734) with CHCl3 elution followed by conventional chromatography over 20 g. of silica (E. Merck 7734) packed in benzene-ethyl acetate (95:5) and elution with this solvent mixture provided, after workup, a yellow solid, m.p. 60°-62°.