Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>CN(C)C=O.N1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[NH:16][C:13](=[O:15])[CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=[CH:3][CH:4]=1
Reactant: O=C(O)Cc1ccnc2ccccc12
Reactant: Nc1cnccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccnc2ccccc12)Nc1cnccn1
Temperature: 80 °C
Reaction time: 9 h
Yield: 62 %

Procedure:
A solution of 200 mg (0.89 mmol) of quinolin-4-yl-acetic acid hydrochloride salt and 145 mg (0.89 mmol) of N,N-carboyl diimidazole was stirred in 3 ml of dimethylformamide at RT for 2 h. 2-Aminopyrazine (63 mg, 0.66 mmol) in 2 ml of pyridine was added dropwise over 10 mins and stirred at 80° C. for a further 9 h. The solution was allowed to cool, concentrated in vacuo, and partitioned between dichloromethane and water. The organic layer was washed 3 times with water, concentrated in vacuo and the material purified by chromatography. White solid. Amount 108 mg. Yield 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([O:31]C1C=CC=CC=1)=O)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:41][CH:38]1[CH2:40][CH2:39]1)=[O:31])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)c2cc1C(=O)OC
Reactant: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)OC

Procedure:
Methyl 4-[3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-7-(2-methoxyethoxy)-6-quinolinecarboxylate (3.2 g), cyclopropylamine (1.3 ml) and dimethylformamide (20 ml) were stirred together at 60° C. for 10 minutes. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=50:1, 20:1) to obtain 2.26 g of the target substance as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[N:37][NH2:38])[NH2:36]>ClCCl.O>[NH2:36]/[C:35](/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)=[N:37]\[NH:38][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: NN=C(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To as solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid 37 g (167 mM) in dichloromethane (300 ml) is added carbonyl diimidazole (1 eq.) in small portion over a period of 30 min. pyridine-2-carbohydrazonamide is then added to reaction mixture and stirred at room temperature for 3 hrs. Dichloromethane is evaporated and reaction mass is then stirred in water for 30 min. solid precipitated is filtered and dried to afford the desired compound.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[OH-].[Na+].Br[CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1.O>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]#[N:9])[CH2:15][CH2:14]2)[CH:2]=1
Reactant: ClCCBr
Reactant: Cc1cccc(CC#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C2(C#N)CC2)c1
Temperature: 60 °C

Procedure:
To a stirred solution of 2-(m-tolyl)acetonitrile (4.2 g, 32 mmol) in toluene (15 mL) was added sodium hydroxide (30 mL, 50% w/w in water, 375 mmol), 1-bromo-2-chloroethane (9.3 mL, 112 mmol) and (n-Bu)4Br (0.5 g, 1.55 mmol). The mixture was heated at 60° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10]2)=[CH:5][CH:4]=1.N.S(=O)(=O)(O)[OH:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:19])[CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(-n2ncc(C#N)c2N)cc1
Agent: N
Product: COc1ccc(-n2ncc(C(N)=O)c2N)cc1
Temperature: 0 °C

Procedure:
1.5 g of 1-(4-methoxyphenyl)-5-amino-4-pyrazolecarbonitrile were stirred at 10°-15° C. with 10 ml of concentrated sulphuric acid until all of the solid had dissolved. The mixture was poured on to 60 g of crushed ice and made basic with concentrated ammonia solution. The precipitated product was filtered off, washed with water and recrystallized from ethanol to give 900 mg of 1-(4-methoxyphenyl)-5-amino-4-pyrazolecarboxamide of melting point 213°-215° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([O:15][CH:16]([CH3:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:14])[CH3:13].O>ClCCCl>[C:12]([O:15][CH:16]([CH3:24])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:20][CH:19]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)Cc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)OC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Succinic anhydride (3 g) was added, under a nitrogen atmosphere, to a stirred slurry of aluminium chloride (8.25 g) in 1,2-dichloroethane (50 ml). The resulting mixture was stirred at room temperature for 15 minutes. A solution of 2-acetoxypropyl benzene (5 g) in 1,2-dichloroethane (20 ml) was added, dropwise, to the stirred mixture which was stirred for a further 3 days at room temperature. The reaction mixture was poured into water. The organic solvent was evaporated and the aqueous residue was extracted into ethyl acetate. The organic extract was washed with 2N HCl and extracted into dilute sodium bicarbonate solution. The aqueous extract was acidified with 2N HCl and extracted into ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil which was chromatographed on silica gel. Elution with petroleum ether(60-80) - diethyl ether(50:50) gave 3-[4-(2-acetoxypropyl)- benzoyl]propionic acid as an oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(=O)(O)[O-].[Na+].O.[Cl:11][C:12]1[N:17]=[C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:15]2[N:26]([CH2:38][C@H:39]3[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]3)[C:27]([N:29]3[CH2:34][CH2:33][O:32][C@@H:31]4[CH2:35][CH2:36][CH2:37][C@@H:30]34)=[N:28][C:14]=2[CH:13]=1>CCO>[Cl:24][C:22]1[CH:23]=[C:18]([C:16]2[C:15]3[N:26]([CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]4)[C:27]([N:29]4[CH2:34][CH2:33][O:32][C@@H:31]5[CH2:35][CH2:36][CH2:37][C@@H:30]45)=[N:28][C:14]=3[CH:13]=[C:12]([Cl:11])[N:17]=2)[C:19]([N:3]([CH3:4])[CH3:2])=[N:20][CH:21]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)c1ncc(Cl)cc1-c1nc(Cl)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 90 °C

Procedure:
To a solution of dimethylamine hydrochloride (580 mg, 7.25 mmol) and sodium bicarbonate (812 mg, 9.67 mmol) in EtOH:water (4 mL:2 mL) was added 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic) (125 mg, 0.24 mmol). The reaction was heated to 90° C. for 5 hours. The reaction was then concentrated and diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 45% EtOAc/hexanes) afforded 5-chloro-3-{6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-4-yl}-N,N-dimethylpyridin-2-amine (racemic). MS ES calc'd. for C28H36Cl2N6O [M+H]+ 543. found 543.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[CH3:6])=[N:11][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
2,5-hexanedione (46.2 g, 0.41 mol) was added to a suspension of 2-amino-5-bromopyridine (50.0 g, 0.29 mol) and the reaction heated to reflux for 24 hours under Dean and Stark conditions. para-Toluene sulfonic acid (100 mg) was added and the reaction was refluxed for a further 18 hours. 8 ml of water were removed, so the reaction was cooled to room temperature, washed with water (100 ml) and passed through a plug of silica gel, eluting with toluene. The eluent was concentrated in vacuo and the residue dissolved in pentane:dichloromethane (1:1 by volume) and passed through a plug of silica gel, eluting with pentane:dichloromethane (1:1 by volume). The eluent was concentrated in vacuo to give a red liquid, which solidified on standing. The solid was recrystallised from isopropanol to give the title compound as a pale yellow solid (54.4 g).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([OH:17])(=[O:16])[CH3:15].[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1O)([CH3:20])[CH3:19]>O>[C:14]([O:17][C:22]1[C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:27]([CH3:29])[CH3:28])(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CC(=O)Oc1c(C(C)C)cccc1C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
3.45 g (16.4 mmol) of trifluoroacetic anhydride is added to 0.83 ml (14.6 mmol) of acetic acid at 0° C. while leaving the mixture to return to ambient temperature over 2 hours. The mixture is then cooled down to 0° C. and 1.95 g (11.0 mmol) of 2,6-diisopropylphenol is added dropwise. The reaction medium is maintained under stirring for 12 hours before being poured into ice-cooled water. After extraction with dichloromethane, the organic phase is washed with sodium chloride in a saturated aqueous solution before being dried over magnesium sulphate, filtered and concentrated under vacuum. A colourless oil is obtained with a yield of 86%. This product is sufficiently pure to be used directly in the following stage.
Reaction SMILES: Br[C:2]1([F:10])[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6].NCCN>[Ni].C(O)C>[F:10][CH:2]1[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1CC1(F)Br
Agent: [Ni]
Solvent: NCCN
Solvent: CCO
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
An internal glass tube was introduced into an autoclave and 0.5 g of ethyl 2-bromo-2-fluoro-1-cyclopropanecarboxylate (cis:trans=0.8:1), 0.5 ml of Raney nickel and 5 ml of ethanol were fed thereinto. Then 0.43 g of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under a hydrogen gas atmosphere (1 kgf/cm2) for 24 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture containing the title compound was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 100%, the yield was 78% and the cis:trans ratio was 0.8:1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]1[CH2:17][CH2:16][O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]1=2
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of Ethyl 2-(3,4-dihydroxyphenyl)acetate (1.11 g, 5.66 mmol) and 1,2-dibromoethane (1.07 g, 5.69 mmol) in DMF (5 mL) was added cesium carbonate (3.71 g, 11.4 mmol). The reaction mixture was stirred for 2 hrs at 80° C. then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:4-1:2) as eluant.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27]C1C=CC(C2C=C3N=C(CCC4NC(=S)CCCC4)NC3=NC=2)=CC=1.N>CO>[CH3:26][O:27][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Agent: N
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 98 mg of 7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepane-2-thione (compound A3) and 6.0 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 5 days. Purification by flash chromatography on LiChroprep-NH2® (eluent: ethanol) affords 23 mg of the title compound as an amorphous, colorless solid of m.p. 306° C. ESI-MS: 364.2 (MH+). TLC: Rf=0.50 (LiChroprep-NH2® HPTLC, methanol/water 10:1 parts by volume).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:10])=[CH:13][CH:14]=1
Reactant: Nc1nccs1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Nc1nccs1
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (0.3 g, 1.4 mmol) in DCM (10 ml) was added triethylamine (0.23 ml, 1.68 mmol) and HOBt (0.23 g, 1.68 mmol) at 0° C. After stirring at this temperature for 5 min. added 2-aminothiazole (0.168 g, 1.68 mmol) and followed by EDCI (0.332 g, 1.68 mmol). The resulting solution was stirred for 12 h. then quenched with saturated aqueous NH4Cl solution (15 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL). The organic phase was successively washed with 2% HCl (50 mL), brine (50 mL) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:10 ethyl acetate:hexanes) to give 2-(4-Chloro-phenoxy)-2-methyl-N-thiazol-2-yl-propionamide (0.325 g, 78%). 1H NMR (400 MHz, CDCl3): δ 1.58 (s, 6H), 6.76 (d, J=8.8 Hz, 2H), 7.01 (d, J=3.6 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.50 (d, J=3.6 Hz, 1H), MS (EI) m/z 296.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27]C1C=CC=CC=1C1CCC2C(=CC=C(O)C=2)O1>>[Cl:27][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:12]=2)[O:17]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1Cl)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2Cl)O3)nc1

Procedure:
2-[2-(2-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 485 mg of 2-(2-chlorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9, 0.5 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.62 (dd, 1H, J 7.5, 1.8 Hz), 7.51 (dd, 1H, J 7.6, 1.7 Hz), 7.45-7.40 (m, 2H), 7.21 (dd, 1H, J 9.1, 0.5 Hz), 7.04 (d, 1H, J 2.7 Hz), 6.99 (dd, 1H, J 8.8, 2.7 Hz), 6.94 (d, 1H, 8.8 Hz), 5.40 (dd, 1H, J 10.4, 2.1 Hz), 3.04 (m, 1H), 2.80 (m, 1H), 2.24 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[C:10](=[O:18])[CH:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:25]([N:38]1[CH2:43][CH2:42][N:41]([C:15](=[O:17])[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10]2=[O:18])[CH2:40][CH2:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1c1ccccc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-(tert-butoxycarbonyl)-2-oxo-3-phenylpiperazin-1-yl)acetic acid (Example 101C, 0.334 g, 1 mmol) and 1-benzhydrylpiperazine (0.252 g, 1 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.38 g, 1 mmol) and diisopropylethylamine (0.8 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed sequentially with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.44 (m, 6H), 7.30 (m, 7H), 7.19 (m, 2H), 5.74 (m, 1H), 4.51 (d, J=15.60 Hz, 1H), 4.23 (s, 1H), 4.12 (q, J=7.12 Hz, 1H), 3.96 (d, J=15.94 Hz, 1H), 3.59 (m, 3H), 2.38 (m, 5H), 1.44 (s, 9H); MS (ESI+) m/z 569 (M+H)+.
Reaction SMILES: O.CO[CH:4](OC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:16]>ClC1C=CC=CC=1>[CH3:16][C:8]1[C:7]2[O:6][CH:5]=[CH:4][C:12]=2[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=1
Reactant: COC(COc1cc([N+](=O)[O-])ccc1C)OC
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c2ccoc12
Temperature: 25 °C
Yield: 38 %

Procedure:
Add Amberlyst® 15 ion-exchange resin (36 g) to chlorobenzene (700 mL). Heat the reaction mixture to reflux and azeotrope out water, to dry the resin. Dissolve 2-(2,2-dimethoxyethoxy)-1-methyl-4-nitrobenzene (34.8 g, 144 mmol) in chlorobenzene (125 mL) and add dropwise to the stirring, refluxing reaction mixture under nitrogen over 15 minutes. Continue refluxing for 1.5 hours. Cool to room temperature, filter to remove the resin and concentrate under reduced pressure. Dissolve the residue in hexane, diethyl ether (1:1), wash with 0.5 M aqueous sodium hydroxide, aqueous saturated sodium chloride, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Chromatograph on flash silica using hexane, ethyl acetate (9:1) and recrystallize from hexane, toluene (1:1) to obtain the desired compound as a yellow solid (9.7 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[CH:23]=[C:24]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:13])=[CH:7][CH:8]=1)(=[O:29])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 45 mL of DMF. To the stirred solvent was added 3-(4-Hydroxy-phenyl)-propanoic acid methyl ester (4.5 g, 16.35 mmol) followed by K2CO3 (6.78 g, 49.074 mmol) and the resulting mixture stirred at room temperature for 30 minutes. (3-bromomethyl-phenyl)-phenyl-methanone (2.94 g, 16.35 mmol) was added to the above mixture and stirring continued at RT for 24 h. After completion of the reaction (reaction monitored by TLC), reaction solvent was removed under reduced pressure. The crude compound was purified by column chromatography on silica gel (100/200 mesh) using petroleum ether (60-80) and ethyl acetate as eluent which yielded the product as yellow color oil (5.1 g, Yield: 83.3%): MS (ESI, 120 eV): m/z=375.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.68 (s, 1H), 7.62-7.66 (d, 3H), 7.57-7.59 (d, 1H), 7.53 (m, 1H), 7.45-7.50 (m, 3H), 7.11-7.13 (d, 2H), 6.88-6.90 (d, 2H), 5.10 (s, 2H), 3.66 (s, 3H), 2.85-2.92 (m, 2H), 2.56-2.62 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Phenyl-thiazol-2-ylamine (35.2 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse -phase preparative liquid chromatography (20.6 mg, 0.0635 mmol, 31.8%). ESI-MS m/z calc. 294.1, found 295.2 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1cccn1-c1ncccn1
Temperature: 130 °C
Reaction time: 13 h
Yield: 27.2 %

Procedure:
A mixture of 1.9 g of 2-pyrrolecarbaldehyde, 2.3 g of 2-chloropyrimidine, 7.8 g of cesium carbonate and 20 ml of N-methylpyrrolidone was stirred at 130° C. for 13 hours, and then allowed to cool to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.94 g of 1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde of the formula: