Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:17]C)[CH2:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@H:7]1[OH:16])C.N.CCO>CCOCC>[CH3:17][N:3]([CH3:1])[CH2:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH2:8][C@H:7]1[OH:16]
Reactant: CCN(CC)CC[C@@H]1Cc2ccccc2C[C@H]1O
Agent: N
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CC[C@@H]1CC2=C(CC=CC2)C[C@H]1O
Reaction time: 0.17 h

Procedure:
A solution of 14.6 g (66.6 mmol) of trans-3-[2-(diethylamino)ethyl]-1,2,3,4-tetrahydro-2-naphthalenol (prepared as in Example 10) in 125 ml of ether is added to 1 liter of NH3 (liquid). To this stirred solution is added 10 l g of Li in pieces over 10 minutes. When the addition is complete, the reaction mixture is stirred for 30 minutes, after which time absolute EtOH (~ 150 ml) is added dropwise until the blue color is discharged. The NH3 is then allowed to evaporate, the residue is diluted with water, and this thoroughly extracted with ether. The combined ether extracts are washed with saturated aqueous NaCl, dried, and concentrated in vacuo to 13.4 g (92%) of the title compound as an oil.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[C:33]2[C:28](=[CH:29][C:30](O)=[CH:31][CH:32]=2)[CH:27]=[C:26]([NH:35][C:36]2[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=2)[N:25]=1.C(N(CC)CC)C>ClCCl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[C:24]([C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[F:16])=[N:25][C:26]([NH:35][C:36]1[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=1)=[CH:27]2)(=[O:8])=[O:9]
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (204.4 mg) in 5 mL of dichloromethane was added to the mixture of 1-(2,4-difluoro-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (170 mg, 0.48 mmol) and triethylamine (145.4 mg) in 20 mL of dichloromethane by syringe at 0° C. The solution was stirred at room temperature overnight, and was diluted with dichloromethane (20 mL). The organic layer was washed with 10% hydrochloric acid, sodium bicarbonate, saturated sodium chloride, and evaporated to give an oil which was used for the next reaction without further purification.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[C:11]([CH:16]([C:25]3([CH3:28])[CH2:27][CH2:26]3)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=2[Cl:15])=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]([C:25]2([CH3:28])[CH2:26][CH2:27]2)[CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C(CC(=O)OC(C)(C)C)C3(C)CC3)ccc2Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C1(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
159 mg (0.29 mmol) of tert-butyl 3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)propanoate were taken up in 7 ml of dichloromethane and 1.2 ml of water. 145 mg (0.64 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were then added, and the reaction solution was stirred at room temperature for 2 h. The reaction mixture was then added to 10 ml of saturated aqueous sodium bicarbonate solution. The phases were separated, and the aqueous phase was then extracted three more times with in each case about 10 ml of dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC (mobile phase methanol/water). This gave 31 mg of the target product (34% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](I)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.C(O[CH2:39][CH3:40])(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11]([C:40]3[CH:39]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc3ccccc3c1)=CCC2c1ccccc1
Yield: 67 %

Procedure:
240 mg of tetrakis(triphenylphosphine)palladium and then a solution of 0.69 g of 2-naphthylboronic acid, isolated in the trimer anhydride form, in 20 cm3 of methanol were added to a solution of 2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 40 cm3 of toluene. 45 cm3 of a 2N aqueous sodium carbonate solution were added dropwise and the reaction mixture is brought to reflux for four hours. After cooling, 80 cm3 of water and 60 cm3 of ethyl acetate were added. The organic phase was separated by settling, washing with water to neutrality and dried over magnesium sulphate. After concentrating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume). 1.33 g (67%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(2-naphthyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a white foam, the characteristic of which was as follows:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:32][C:30]3[CH:29]=[CH:28][C:27]([O:34][CH3:35])=[C:26]([CH:31]=3)[C:25]([OH:36])=[O:24])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1coc(Cn2cc(C3CCNCC3)c3cccnc32)c1
Product: COc1ccc(CN2CCC(c3cn(Cc4ccco4)c4ncccc34)CC2)cc1C(=O)O
Yield: 76 %

Procedure:
This compound was prepared following the procedure described in example 7, part G and H starting with 2.37 g (8.4 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 3 g (11 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification the overall yield was 76% (1.6 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].S(Cl)([Cl:12])(=O)=O>CCCCCC>[Cl:12][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5](=[O:7])[CH3:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)CCC(C)C
Solvent: CCCCCC
Product: CC(=O)C(Cl)CC(C)C
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a refluxing solution of 750 g (6.58 mol) 5-methyl-2-hexanone in 1.13 1 n-hexane at 65° C., 1.06 kg (7.89 mol) sulfuryl chloride was added over a period of 2 h. After complete addition of the sulfuryl chloride, the reaction mixture was allowed to cool to room temperature, was washed 4 times with 150 ml H2O, dried (MgSO4) and concentrated in vacuo. The residue was distilled over a 5 cm Vigreux-column (80 mbar, 67-76° C.) to give 884 g of 3-chloro-5-methyl-2-hexanone in the form of a yellowish liquid (purity: 88%, impurity: 11% 3,3-dichloro-5-methyl-2-hexanone).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])=[CH:12][C:11]=1[Cl:23])(=O)C.[OH-].[Na+].O.Cl>CO>[Cl:22][C:20]([Cl:21])=[CH:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]([Cl:23])[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[C:15]([Cl:16])[CH:14]=1
Reactant: CC(=O)OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Twenty seven grams (0.067 mole) of 4-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]butyl acetate was stirred and a solution of 5.4 grams (0.134 mole) of sodium hydroxide in 300 mL of methanol was added portion-wise. Upon completion of addition the reaction mixture was stirred at ambient temperature during a two hour period. After this time the reaction mixture was stirred with 400 mL of water and was neutralized with concentrated hydrochloric acid. The neutral mixture was extracted with four 150 mL portions of diethyl ether, and the combined extracted were washed with one 150 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, yielding 22.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][OH:13].[C-]#N.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[OH:13][NH:12][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To methyl phenylacetate (0.288 mL, 2.0 mmol) in THF:MeOH: 50% aqueous NH2OH (1:1:0.5, 2.5 mL) was added KCN (5 mg, 0.08 mmol, 4 mol %) and the mixture was stirred at ambient temperature. After 2 h the reaction was complete by HPLC. To the mixture was added saturated aqueous citric acid (25 mL) followed by extraction with EtOAc (3×25 mL). The organic phase was isolated, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase HPLC (C-18, 5μ 100×30 mm column), eluting with a gradient of acetonitrile: water (0.05% TFA). Following lyophilization of the product fractions there was obtained pure N-hydroxy-2-phenylacetamide as a fluffy solid (0.234 g, 77% yield): LRMS (M+H)+: 152.1 m/z; 1H NMR (DMSO-d6) δ: 10.6(s, 1H), 8.81(s, 1H), 7.2(m, 5H), 3.26(s, 2H); Anal (C,H,N): % C: (calc) 63.56; (found) 63.63; % H: (calc.) 6.00; (found) 5.91; % N: (calc.) 9.27, (found) 9.04.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1F.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1[N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1c(F)c(F)nc(F)c1Cl
Temperature: 40 °C
Reaction time: 24 h
Yield: 102.6 %

Procedure:
To a mixed solution of 40 ml dichloromethane and 20 ml N,N-methylformamide were added 18.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine and 20.5 g potassium phthalimide, and the mixture was stirred at 40° C. for one day. After adding 40 ml of chloroform, the mixture was washed twice with 500 ml of distilled water and once with 500 ml of 0.5% aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersed in diisopropylether, and collected by filtration to obtain 32.0 g of the title compound as a colorless powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:19]([NH2:21])=[O:20])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][CH2:16][NH2:17])[C:7]=2[N:18]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:22]([NH:17][CH2:16][CH2:15][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:5]=[C:4]([C:19]([NH2:21])=[O:20])[C:3]([NH2:2])=[N:18][C:7]1=2)(=[O:24])[CH3:23]
Reactant: NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (16, 50.0 mg, 0.186 mmol) in pyridine (2 mL) was added DMAP (23.0 mg, 0.188 mmol) and acetic anhydride (23 μL, 0.243 mmol). The reaction was stirred at RT under an atmosphere of argon. After 1 h, the reaction was concentrated and the crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to yield 9-[2-(acetylamino)ethyl]-2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (22, 11 mg, 19%). NH4OAc standard conditions. DAD Retention time=5.18 min. M+H=312. 1H NMR (300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.01 (t, J=5.7 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.58 (br s, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.33 (t, J=8.1 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 4.31 (t, J=6.0 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H), 1.71 (s, 3H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[N:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Brc1ncccn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromopyrimidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])([OH:22])=[O:21]>C(O)C.C1(C)C=CC=CC=1>[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1/[CH:34]=[CH:15]/[C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=2)([OH:22])=[O:21]
Reactant: Cc1cccc[n+]1CCCCCC(=O)O
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC)c1ccc2cc(/C=C/c3cccc[n+]3CCCCCC(=O)O)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromen-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-2-methyl-pyridinium bromide are converted according to the general directions above. Column chromatography: SiO2, eluent: ethanol/toluene.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)#[N:13].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)#[N:13]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: N#Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2C#N)nc1
Temperature: 25 °C
Yield: 14 %

Procedure:
Methyl 6-chloronicotinate (1.00 g, 5.83 mmol) and (2-cyanophenyl)boronic acid (856 mg, 5.83 mmol) were added to 1,4-dioxane (50 mL). To this was added 14.6 mL of a 2 M solution of aqueous potassium carbonate and tetrakis(triphenylphosphine)palladium(0) (337 mg, 0.291 mmol). The above reagents were heated at reflux for 5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (20 mL), the phases were separated and the organic layer was dried over anhydrous MgSO4, filtered and evaporated to a gum. The solid was purified using chromatography on silica eluting with a mixture of heptane: ethyl acetate 80:20, 70:30, 30:70. The product fractions were combined and evaporated to give methyl 6-(2-cyanophenyl)nicotinate as a white solid (195 mg). LCMS (ES+) 239 (M+1), 1.37 minutes; 1H NMR (400 MHz CDCl3) ppm 4.00 (s, 3H) 7.58 (t, J=7.4 Hz, 1H) 7.74 (d, J=6.2 Hz, 1H) 7.85 (d, J=7.8 Hz, 1H) 7.90 (m, 2H) 8.45 (dd, J=5.8, 2.4 Hz, 1H) 9.37 (d, J=2.0, Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[F:25][C:10]([F:9])([F:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20]([CH:22]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Reactant: Nc1ccccc1O
Product: Oc1ccccc1N=Cc1ccc(-c2ccccc2C(F)(F)F)o1

Procedure:
Using 2-Aminophenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.53 g of 2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:30][SiH:31]([CH3:33])[CH3:32])([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]=O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][O:37]CC1.O>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:30][SiH:31]([CH3:32])[CH3:33])([C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22][C:23]4[CH:24]=[CH:4][CH:3]=[CH:2][C:11]=4[C:39]([CH:38]=[O:37])=[O:34])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[SiH](C)O[C@](CCCC=O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Reactant: C1COCCO1
Solvent: O
Product: C[SiH](C)O[C@](CCc1ccccc1C(=O)C=O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Temperature: 25 °C

Procedure:
To predissolved SeO2 (2.95 g, 26.57 mmol) in dioxane/H2O mixture (100 mL:0.48 mL) at 60∞C, was added the ketone from Step 1 (14.4 g, 26 mmol) in solution in dioxane (70 mL). The reaction mixture was heated at 100∞C overnight. The reaction was cooled to room temperature and filtered through a pad of celite and washed with dioxane (20 mL). Evaporation to dryness yielded the title compound which was used as such in the next step (Crude weight 14 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:19][CH2:18]1.O>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Solvent: O
Product: COc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 78.8 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine; yield 78.8% of theory; the hydrochloride, after recrystallization from water and drying, contained 0.486 mol water; m.p. 174°-175°C;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[C:31]([C:33](=[O:38])[NH:34][CH:35]5[CH2:37][CH2:36]5)[CH:30]=[CH:29][C:28]=4[CH3:39])[CH:25]=3)[C:20](=[O:40])[N:19]([CH2:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.N>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[C:31]([C:33](=[O:38])[NH:34][CH:35]5[CH2:36][CH2:37]5)[CH:30]=[CH:29][C:28]=4[CH3:39])[CH:25]=3)[C:20](=[O:40])[N:19]([CH2:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)NC3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step i) (0.1 g) in dichloromethane (9 mL) was added trifluoroacetic acid (1 mL) and the mixture stirred at room temperature for 1 hour. The reaction was basified by the addition of 0.88 ammonia and washed with water. The organics were dried over magnesium sulphate, filtered and concentrated to dryness to yield the title compound as a solid (0.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:30])=[CH:27][N:26]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)NCc2ccccc2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 443.1 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[Cl:14]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:14][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:13])=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2nccc(O)c2c1
Solvent: CC(=O)O
Product: COc1ccc2ncc(Cl)c(O)c2c1
Temperature: 60 °C
Yield: 96.2 %

Procedure:
6-Methoxy-quinolin-4-ol (18.5 g) in acetic acid (750 mL) was treated with N-chlorosuccinimide (15.52 g) and the mixture was heated at 60° C. for 4.5 hr, cooled, and evaporated. Excess sodium bicarbonate solution was added and the solid collected and washed with water and dried in vacuo at 40° C. overnight, to give a yellow solid (21.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.[H-].[Na+].[CH2:21](I)[CH3:22]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:21][CH3:22])[N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1
Reactant: CCI
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21

Procedure:
To 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.418 mmol), NaH (60% in oil, 2.1 mmol) and ethyl iodide (2.1 mmol) is added N-methylpyrrolidinone (1 mL). After 5 min the reaction mixture is heated in the microwave at 175 C for 10 min. Reverse phase HPLC gave the product.