Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]1O)=[O:4].CS(Cl)(=O)=O.O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)C1CCC[C@]2(CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)C1O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C1=C[C@]2(CCC1)CC[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.3 %

Procedure:
To a solution of the crude (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (1.76 g) obtained in Step 5 in pyridine (5 mL) was added methanesulfonyl chloride (0.25 mL) under ice-cooling, followed by stirring the mixture at room temperature for 15 hours. Then, to the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was dissolved in tetrahydrofuran (10 mL). To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 mL), followed by stirring the mixture at 70° C. for 3.5 hours. After cooling down to room temperature and adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:30 to 1:25) to give (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en e-7-carboxylic acid methyl ester (0.615 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([Br:22])[CH:3]1[CH2:20][CH3:21]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC)C2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC)C2Br
Temperature: 25 °C

Procedure:
To a solution of ethyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetate (19.8 g., 0.060 mole) in carbon tetrachloride (200 ml.) is added N-bromosuccinimide (11.32 g., 0.0636 mole) and α,α1 -azodiisobutyronitrile (425 mg.). The mixture is heated at reflux for 10 minutes, cooled to room temperature and filtered to remove succinimide. The filtrate is washed with water and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to afford ethyl (1-oxo-2-ethyl-3-bromo-6,7-dichloro-5-indanyloxy)acetate which is dissolved in pyridine (40 ml.) and heated at 80° C. for 30 minutes. The solution is then cooled to room temperature and poured into 1.2 N hydrochloric acid (400 ml.). The product is extracted with chloroform and the combined extracts are washed with water and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to afford 16.8 g. of a crude product which is then recrystallized from methanol to afford substantially pure ethyl (1-oxo-2 -ethyl-6,7-dichloroinden-5-yloxy)acetate, m.p. 141°-143° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:18]O>C(OCC)C>[CH3:18][O:4][C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)[C@H](O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of (R)-2-hydroxy-3-phenylpropionic acid (1.5 g, 12.9 mol) in methanol (18 mL) at 0° C. was added concentrated sulfuric acid (0.2 mL). The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature for 24 h. Concentration in vacuo gave a residue which was diluted with diethyl ether (200 mL) and washed with water, saturated sodium bicarbonate and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated in vacuo giving a white solid 1.62 g (85%), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:43]2[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=2)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40].O>ClCCl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:43]2[CH:51]=[CH:50][C:46]([C:47]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:21][CH2:22]3)=[O:48])=[CH:45][CH:44]=2)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40]
Reactant: COc1cc(-c2ccc(C(=O)Cl)cc2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(-c2ccc(C(=O)N3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cc2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) was dissolved in dichloromethane (0.9 mL), and a saturated aqueous solution (0.9 mL) of sodium hydrogencarbonate was added to the solution. 4-(3,4,5-Trimethoxyphenyl)benzoyl chloride (55 mg) was then added dropwise to the mixture under ice cooling, and the resultant mixture was stirred for 1 hour. After water was added to the reaction mixture to conduct extraction with chloroform, the resultant organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C:6]([CH3:19])([C:7]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33](O)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:19])([C:7]3[CH:15]=[CH:14][C:13]([C:16]([O:18][CH:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:17])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)CCC2(C)c3ccc(C(=O)O)cc3CCC12
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(C(=O)OC(c4ccccc4)c4ccccc4)cc3CC[C@@H]12
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Under an atmosphere of nitrogen, 100 mg of 4,10b-dimethyl-8-carboxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one and 66 mg of 1,1'-carbonyldiimidazole were dissolved in 5 mL of anhydrous dimethylformamide and stirred for 1 h. Then 74 mg of benzhydrol was added, and the reaction was stirred for 18 hours, still at ambient temperature. The volatiles were then removed under high vacuum, and the residue was dissolved in 50 mL of dichloromethane and washed with 40 mL of 1N hydrochloric acid, with two 40 mL portions of saturated aqueous sodium bicarbonate, and finally with 40 mL of brine. The organic layer was dried with sodium sulfate, filtered and evaporated under vacuum to give 141 mg of impure product, which was purified by chromatography on silica gel, eluting with ethyl acetate to obtain 91 mg (57%) of the desired product. An analytical sample was recrystallized from ethyl acetate/water. mp 130°-131°. FDMS: m/e=439.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH3:24][C@:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]1(C)CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A mixture of (S)-benzyl 3-(tert-butoxycarbonylamino)-3-methylpyrrolidine-1-carboxylate (29.35 g, 87.77 mmol) and 10% Pd/C (4.670 g, 4.388 mmol) in ethanol (50 mL) was charged with hydrogen (1 atmosphere) and stirred at ambient temperature overnight. The catalyst was removed by filtration and washed with ethanol (2×50 mL). The filtrated was concentrated under reduced pressure to give (S)-tert-butyl 3-methylpyrrolidin-3-ylcarbamate (17.13 g, 85.53 mmol, 97.45% yield) as an oil. MS APCI (+) m/z 201 (M+1) detected.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:25])[NH:18][NH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[C:11]([CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]([O:30][CH2:31][C@H:32]1[O:37][C@H:36](Br)[C@H:35]([O:39][C:40]([CH3:42])=[O:41])[C@@H:34]([O:43][C:44]([CH3:46])=[O:45])[C@H:33]1[O:47][C:48]([CH3:50])=[O:49])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:40]([O:39][C@@H:35]1[C@@H:34]([O:43][C:44](=[O:45])[CH3:46])[C@@H:33]([O:47][C:48](=[O:49])[CH3:50])[C@@H:32]([CH2:31][O:30][C:28](=[O:29])[CH3:27])[O:37][C@H:36]1[O:25][C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[CH3:26])=[C:20]([C:21]([F:24])([F:23])[F:22])[NH:19][N:18]=1)(=[O:41])[CH3:42]
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(F)(F)F)[nH][nH]c1=O
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A suspension of 4-[(4-benzyloxy-2-methylphenyl)methyl]-5-trifluoromethyl-1,2-dihydro-3H-pyrazol-3-one (0.5 g), acetobromo-α-D-galactose (0.62 g) and potassium carbonate (0.29 g) in acetonitrile (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.66 g).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)[CH2:40][CH2:41][CH3:42]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 4-iodo-1-triphenylmethyl-1H-imidazole (Preparation 72, 0.44 g, 0.10 mmol) in dichloromethane (8.0 ml) at room temperature was added slowly ethyl magnesium bromide (3.0 M in diethyl ether, 0.35 ml, 1.0 mmol). After 30 min, tributyltin chloride (0.3 ml, 1.1 immol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 ml) and the product was extracted with dichloromethane (3×10 ml). The combined organic layers were dried (Na2SO4) and concentrated inl vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (10:1 and then 5:1) to give the title compound (59 mg, 98%).
Reaction SMILES: Br.Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[O:12]=[C:13]([CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[C:20]([C@H:29]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[O:30]2)[CH:21]=[C:22]([OH:28])[C:23]=1[O:24][CH2:25][CH2:26][CH3:27])(=[O:17])=[O:16].C(=O)([O-])[O-]>CN(C=O)C>[O:12]=[C:13]([CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[C:20]([C@H:29]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=3)[O:30]2)[CH:21]=[C:22]([O:28][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:23]=1[O:24][CH2:25][CH2:26][CH3:27])(=[O:16])=[O:17]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reactant: BrCCCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCc2cccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 70 °C

Procedure:
3-(3-Bromopropyl)pyridine hydrobromide (51 mg, 0.18 mmol) was added to a solution of trans-2-[3-(2-oxopropylsulfonyl)-4-n-propoxy-5-(2-hydroxy)phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (50.8 mg, 0.1 mmol) [Example 1, Step L] in DMF (2 mL) containing postassium carbonate (28 mg, 0.2 mmol), and the reaction mixture was heated at 70° C. for 1 h. The product was extracted with ethyl ether in the usualy way and purified by preparative TLC (hexane-ethyl acetate; 1.2, v/v) Rf 0.15; MS, m/z 628 (M+1)+. ; NMR (CDCl3)δ d 1.09 (t, J=7.5 Hz, CH2CH2CH3), 1.92 (m, CH2CH2CH3), 2.18 (m, CH2CH2CH2Pyr), 2.37 (s, CH2COCH3), 2.87 (T, CH2CH2CH2Pyr), 3.83 (s, OCH3), 3.88 (s, 2 OCH3), 4.08 (t, CH2CH2CH2Pyr), 4.18 (t, CH2CH2CH3), 4.48 (s, CH2CO), 5.13-5.27 (m, H-2 & H-5), 6.61 (s, 2 H, C5ArH).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.P(Br)(Br)([Br:14])=O>>[Br:14][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ccnc2cccnc12
Product: Brc1ccnc2cccnc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A flask was charged with 1,5-naphthyridin-4-ol (1 g, 6.7 mmol) and phosphorousoxybromide (5 g, 17 mmol). The mixture was heated to 150° C., stirred for 1 hour, and then cooled to room temperature. The mixture was poured into ice-water and extracted with toluene. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was re-crystallized from petroleum ether to give 4-bromo-1,5-naphthyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13](=O)[C:14]3[N:15]([N:17]=[CH:18][CH:19]=3)[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:23])=O>O>[Cl:23][C:13]1[C:14]2[N:15]([N:17]=[CH:18][CH:19]=2)[CH:16]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cn3nccc3c(=O)[nH]2)cc1OC
Solvent: O
Product: COc1ccc(-c2cn3nccc3c(Cl)n2)cc1OC
Temperature: 95 °C

Procedure:
6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4(5H)-one 5.02 (74 mg, 0.27 mmol) was taken up in phosphorous oxychloride (1.4 mL, 15 mmol) and mixture was heated to 95° C. for two hours. After cooling to room temperature, mixture was carefully added via pipet to vigorously stirring water (15 mL) with internal temperature monitoring, at a rate to keep the internal temperature below 45° C. Reaction flask was washed with 15 mL of ethyl acetate and added to aqueous mixture to ensure complete transfer. Layers were separated and aqueous was extracted with ethyl acetate. Combined organic layers were washed with 1:1 brine/saturated NaHCO3 (aq), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 4-chloro-6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazine 5.03. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H13ClN3O2: 290.06; found: 290.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:4]2([CH:8]=[CH:7][CH:6]=[CH:5]2)[CH:3]1[C:9]([OH:11])=[O:10].[C:13]([CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)#[CH:14]>>[CH3:1][C:2]1([CH3:12])[C:4]2([CH:8]=[CH:7][CH:6]=[CH:5]2)[CH:3]1[C:9]([O:11][CH:15]([C:13]#[CH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:10]
Reactant: CC1(C)C(C(=O)O)C12C=CC=C2
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Product: C#CC(OC(=O)C1C(C)(C)C12C=CC=C2)c1cccc(Oc2ccccc2)c1

Procedure:
The procedure of Example 1 is followed using 2,2-dimethylspiro[2,4]hepta-4,6-diene-1-carboxylic acid in place of 2,2-dimethyl-4,5-benzospiro[2,4]hepta-4,6-diene-1-carboxylic acid and α-ethynyl-m-phenoxybenzyl alcohol in place of m-phenoxybenzyl alcohol to give the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][NH:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:25][CH2:26]Cl)[CH3:24]>O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][N:5]([CH2:26][O:25][CH2:23][CH3:24])[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCNC(=O)NOc1cc(Cl)ccc1Cl
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCNC(=O)N(COCC)Oc1cc(Cl)ccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To 2.63 g of 3-(2,5-dichlorophenoxy)-1-n-propylurea, were added 4.14 g (20 mmoles) of anhydrous potassium carbonate and then 1.42 g (15 mmoles) of chloromethyl ethyl ether. The mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and 300 ml of water was added. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane) to give 0.44 g (yield 14 %) of the desired compound as a pale yellow oil.
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O>CS(C)=O.[Cl-].[Na+].O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([N:6]2[C:5]3[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])=[CH:15][CH:14]=1
Reactant: N#C[Cu]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 23.2 %

Procedure:
5-Amino-1-(4-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (0.7398 g) was dissolved in dimethyl sulfoxide (35 ml), and to the solution was added CuCN (0.6065 g). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.792 ml) was added dropwise during 1.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 4 hours. After allowing to cool, to the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (100 g, CHCl3:methanol=25:1) and then by silica gel column (70 g, hexane:ethyl acetate=1:1) to give the title compound (0.1767 g, 23%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][O:34][C:35](=[O:45])[CH2:36][C:37](=[O:44])[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:41]3[CH2:40][CH2:39][N:38]([C:37](=[O:44])[CH2:36][C:35]([O:34][CH3:33])=[O:45])[CH2:43][CH2:42]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: COC(=O)CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)OC(C)(C)C)CC3)s2)CC1
Yield: 24.7 %

Procedure:
Prepared as described in general procedure (P) using 4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester (68 mg, 0.15 mmol), 3-oxo-3-piperazin-1-yl-propionic acid methyl ester hydrochloride (54 mg, 0.19 mmol) and sodium triacetoxy-borohydride (38 mg, 0.18 mmol) to afford 23 mg (25%) of the desired product after purification.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[I:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH3:8]
Reactant: CNc1ccccc1
Reactant: Cc1c(I)ccnc1F
Product: Cc1c(I)ccnc1N(C)c1ccccc1

Procedure:
2-Fluoro-4-iodo-3-methylpyridine (700 mg) in N-methylaniline (2.5 mL) was heated at 180° C. in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was loaded onto a silica gel cartridge, and was eluted with 0-100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32](SC)=[N+:31]([CH3:36])[C:30]=2[CH:37]=1.C(N(CC)CC)C>CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33](=[C:6]3[C:5](=[O:7])[N:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3][CH:2]3[CH3:1])[CH2:32][N:31]([CH3:36])[C:30]=2[CH:37]=1
Reactant: CSc1sc2ccc(Cl)cc2[n+]1C
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1NN(c2ccccc2)C(=O)C1=S1CN(C)c2cc(Cl)ccc21
Reaction time: 1.5 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.51 g,)) was mixed with 3.5 g (0.0087 mol) 5-chloro-2-methylthio-3-methylbenzothiazolium tosylate in 25 ml methanol. Triethylamine (0.89 g,) was added. The mixture was stirred for 1.5 hours, then filtered and washed with methanol. After drying the yield was 2.75 g (89%), mp 206° C., λmax=379 (ε=26,000).
Reaction SMILES: [CH:1]1([O:5][CH2:6][C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH:22]5[CH2:25][NH:26][CH2:27][CH:21]45)=[CH:16][CH:15]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[CH:1]1([O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH:22]5[CH2:25][N:26]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:27][CH:21]45)=[CH:16][CH:15]=3)=[O:12])=[CH:28][CH:29]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCC3CNCC32)cc1)c1ccc(COC2CCC2)cc1
Reactant: CN(C)CC(=O)O
Product: CN(C)CC(=O)N1CC2CCN(c3ccc(NC(=O)c4ccc(COC5CCC5)cc4)cc3)C2C1

Procedure:
4-Cyclobutoxymethyl-N-[4-(hexahydropyrrolo[3,4-b]pyrrol-1-yl)phenyl]-benzamide was reacted with N,N-dimethylglycine by method E. The product with the molecular weight of 476.62 (C28H36N4O3); MS (ESI): 477 (M+H+) was obtained in this way.