Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].CCO.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:15][OH:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This material was prepared from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc., Perkin Trans I 1979, 643). To a solution of 4-cyanobenzaldehyde (1.31 g, 10 mmol) in 1:1 EtOH:pyridine (10 mL) was added hydroxylamine hydrochloride (0.70 g, 10 mmol). The resulting solution was stirred at room temperature for 18 h and was concentrated in vacuo to one-half volume. To this solution was added ice water, causing the product to crystallize from solution. Recrystallization from EtOH--water followed by drying over P2O5 afforded 1.46 g (100%) of the desired oxime; mp: 167.8°-169.4° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:14][CH:10]1[CH2:13][CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
An ethanolic solution of t-butyl bromoacetate (39 g, 0.2 mol) was added dropwise to a stirred chilled ethanolic solution containing cyclobutyl amine (28.4 g, 0.4 mol) and triethylamine (25.3 g, 0.25 mol). After stirring overnight at room temperature, the reaction mixture was concentrated and the residue redissolved in methylene chloride (300 ml). This solution was washed with water (3×500 ml), dried over MgSO4, filtered, and evaporated to dryness, yielding 24.9 g (67%) of the desired product as a light brown oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH2:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[CH3:16]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:20]1[CH2:21][CH2:22][N:17]([CH2:15][CH3:16])[CH2:18][CH:19]=1)(=[O:3])=[O:4]
Reactant: CCN1CCC(=O)CC1
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Product: CCN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 59.1 %

Procedure:
Beginning with 1.50 gm (7.1 mMol) 5-methanesulfonylamino-1H-indole and 1.25 mL (9.3 mMol) 1-ethyl-4-piperidone, 1.34 gm (58.8%) of the title compound were recovered as a light yellow, crystalline powder.
Reaction SMILES: [CH2:1]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.O>[Br:21][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCc1ccsc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
3-Octylthiophene (45 g) was dissolved in DMF (327 mL). NBS (40.75 g) was dissolved in DMF (300 mL) and was subsequently added dropped to the 3-octylthiophene solution at room temperature under the darkness. The reaction mixture was subsequently stirred at room temperature overnight, slowly diluted with water (800 mL) and extracted with diethyl ether (3×300 mL). The combined organic extracts were subsequently washed with brine (2×200 mL) and water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated. Vacuum distillation of the crude residue afforded the title compound as a colorless liquid (56.0 g, yield: 89%): 1H NMR (300 MHz, CDCl3, ppm) δ: 7.15-7.13(d, 1H), 6.78-6.76(d, 1H), 2.57-2.52(t, 2H), 1.59-1.54(m, 2H), 1.29-1.27(m, 10H), 0.90-0.86(t, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[F:18][C:19]([F:33])([F:32])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:26]3[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=3[O:20][C:19]([F:18])([F:32])[F:33])[CH:27]=[O:28])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: O=Cc1ccc(OC(F)(F)F)c(B(O)O)c1
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
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: Cc1ccccc1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Yield: 64.9 %

Procedure:
A solution of Compound 1A (1 g, 3.38 mmol) in 17 mL of toluene was added to a flask containing 2-trifluoromethoxy-5-formyl-phenyl boronic acid (0.95 g, 4.05 mmol), prepared by the procedure described in WO 03/075924, and tetrakis(triphenylphosphine)palladium(0) (195 mg, 0.17 mmol) in 4 mL of toluene. Next, 3.4 mL of a 2M solution of potassium carbonate was added and the reaction heated to reflux for four hours, after which the reaction was cooled and partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous layer was further extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried with sodium sulfate, filtered, stripped and purified via flash chromatography (15% EtOAc/hexanes) to afford 890 mg of product Compound 2A (65%). MS (electrospray): mass calculated for C22H22F3NO3, 405.16; m/z found 406.2, [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][C:10]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)CN(C(=O)OCc2ccccc2)CCCc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CN1C(=O)CNCCCc2ccccc21
Reaction time: 4 h

Procedure:
A suspension of 1-tert-butyloxycarbonylmethyl-4-benzyloxycarbonyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine(1.52 g, 3.48 mmol), and 10% palladium on charcoal (0.2 g) in methanol (20 ml) was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through a pad of celite and the filtrate evaporated to give the crude product, which was purified by flash chromatography on silica gel with methanol-DCM(1:12) as eluant. (996 mg, 95%)
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[OH:53][CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:59]4[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][OH:53])[CH2:57][CH2:58]4)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: OCCN1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: CC1C=CC2C(=CC=CC=2N2CCN(CCC3C=C(C=CC=3)N)CC2)N=1.[Cl:27]CCN=C=O.[CH3:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][C:52]3[CH:53]=[C:54]([N:58]4[CH2:62][CH2:61][NH:60][C:59]4=[O:63])[CH:55]=[CH:56][CH:57]=3)[CH2:46][CH2:45]2)[N:35]=1>>[ClH:27].[ClH:27].[CH3:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][C:52]3[CH:53]=[C:54]([N:58]4[CH2:62][CH2:61][NH:60][C:59]4=[O:63])[CH:55]=[CH:56][CH:57]=3)[CH2:46][CH2:45]2)[N:35]=1
Reactant: O=C=NCCCl
Agent: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in 22% yield according to the general procedure for the synthesis of cyclic ureas and carbamates (Method G) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D3) and 1-chloro-2-isocyanatoethane, via the free base 1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCC1CC1
Solvent: CCN(CC)CC
Product: Clc1nc(NCC2CC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(cyclopropyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, aminomethylcyclopropane, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C(CN1C2C(=CC=C3C(=O)C([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)=C(C4C=CC=CC=4)OC3=2)C=N1)#N.I[C:43]1[C:48](=[O:49])[C:47]2[CH:50]=[CH:51][C:52]3[NH:57][C:56](=[O:58])[CH2:55][O:54][C:53]=3[C:46]=2[O:45][C:44]=1[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.CC1(C)C(C)(C)OB(C2C=CC(C3(NC(=O)OC(C)(C)C)CCC3)=CC=2)O1>>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:43]3[C:48](=[O:49])[C:47]4[C:46](=[C:53]5[C:52](=[CH:51][CH:50]=4)[NH:57][C:56](=[O:58])[CH2:55][O:54]5)[O:45][C:44]=3[C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CC#N)c54)c3=O)cc2)CCC1
Reactant: O=C1COc2c(ccc3c(=O)c(I)c(-c4ccccc4)oc23)N1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c5c(ccc4c3=O)NC(=O)CO5)cc2)CCC1
Yield: 52 %

Procedure:
Following the procedure used to prepare tert-butyl (1-(4-(1-(cyanomethyl)-6-oxo-8-phenyl-1,6-dihydropyrano[3,2-g]indazol-7-yl)phenyl)cyclobutyl)carbamate reacted 8-iodo-9-phenylchromeno[8,7-b][1,4]oxazine-3,7(2H,4H)-dione (150 mg, 0.358 mmol), tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (170 mg, 0.455 mmol) was reacted to give the title compound (100 mg, 52%). LCMS (Method I): RT=6.87 min, [M+H]+=539.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=1.C(N(C(C)C)CC)(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][CH:18]([C:12]2[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=[C:10]([NH:9][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:11]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:26][CH:27]=1)#[N:32]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(N)cc(CC)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(NC(=O)C2CCCC2)c1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
Cyclopentanecarbonyl chloride (0.104 ml, 0.85 mmol) was added dropwise at 0° C. to a solution of the ethyl (RS)-(3-amino-5-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (250 mg, 0.772 mmol) obtained in Example 223.4 and diisopropylethylamine (0.146 ml, 0.85 mmol) in CH2Cl2 (5 ml). The reaction mixture was warmed slowly (2 h.) to room temperature. A saturated aqueous solution of KHSO4 was added and the mixture was extracted with EtOAc. The organic phase was washed with H2O, dried and filtered, and the filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane→hexane/EtOAc 2:1). There were obtained 215 mg (66%) of ethyl (RS)-(4-cyano-phenylamino)-[3-(cyclopentanecarbonyl-amino)-5-ethyl-phenyl]-acetate as a colorless foam; MS: 418 ([M−H]−).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH:14]=1)[CH3:5].[Li+].[OH-].C(O)(=O)C>C1COCC1.O>[O:13]1[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:15])=[O:2])=[CH:14][C:10]=2[N:11]=[CH:12]1
Reactant: COC(=O)C(C)c1ccc2ocnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2ocnc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
methyl-2-(benzo[d]oxazol-5-yl)propanoate (2.07 mmol, 425 mg) was dissolved in THF (8 ml) and water (8 m). LiOH*H2O (2.21 mmol, 93 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 40 h, water (25 ml) was added and the pH was set to 3 with acetic acid. The reaction mixture was extracted with dichloromethane and the combined organic phases were dried and filtered over magnesium sulphate. The solvent was removed in a vacuum and the residue was purified by column chromatography (SiO2, dichloromethane/MeOH=15:1). 1H-NMR (CD3OD) δ [ppm]: 8.46 (s, 1H, Ar), 7.70 (d, 1H, J=1.7 Hz, Ar), 7.61 (d, 1H, 8.0 Hz, Ar), 7.42 (dd, 1H, J=8.6, 1.8 Hz, Ar), 3.87 (q, 1H, J=7.1 Hz, CHCH3), 1.51 (d, 3H, J=7.1 Hz, CHCH3).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:7][CH:8]=1
Reactant: OC/C=C/C#Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C/C=C/C#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
In 4 ml of methylene chloride were dissolved 350 mg (1.56 mmol) of (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-yn-1-ol, and 3.5 g of active manganese dioxide were added to the solution, followed by stirring of the resulting mixture at room temperature for 30 minutes. The solid was removed by filtration and the filtrate was concentrated. Then, the filtrate was subjected to column chromatography using 10 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (1:214) to obtain 245 mg (yield: 70%) of the title compound as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]1[C:26]([C:27]([O:29]CC)=O)=[CH:25][CH:24]=[CH:23][N:22]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[N:22]1[C:21]2[CH:9]3[CH2:10][NH:11][CH2:12][CH2:13][N:8]3[C:27](=[O:29])[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cccnc1C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cccnc2C2CNCCN12
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a solution of 2-(3-ethoxycarbonyl-pyridin-2-yl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (may be prepared as described in Intermediate 6; 1.55 g) in DCM (100 mL), TFA (5.0 mL) was added at 0° C. and then reaction mixture was allowed to warm to room temperature. TLC showed disappearance of starting material in 4 h. Reaction mixture was fully evaporated under vacuum to give 1.70 g of crude intermediate. Crude intermediate was dissolved in methanol (100 mL), and then potassium carbonate (4.0 eq) was added. Reaction mixture was stirred at room temperature. TLC showed disappearance of intermediate in 5 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under vacuum to get 800 mg of the crude product. The crude product was purified by column chromatography over 100-200 mesh silica gel by using 0%-10% methanol in chloroform as solvent, which gave the title compound (280 mg).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:4][CH:5]([OH:7])[CH3:6])[CH3:3].[B:9](O)(O)O.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:3])[CH2:4][CH:5]([CH3:6])[O:7][BH:9][O:8]1
Reactant: CC(O)CC(C)(C)O
Reactant: OB(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(C)(C)OBO1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
Into a 3 liter reaction vessel equipped with stirrer, thermometer, reflux condenser and Dean Stark trap is placed 710.0 grams of 2-methyl-2,4-pentanediol; 372.0 grams of boric acid and 500 grams of toluene. With stirring the reaction mass is heated to 87° C. and, by way of the Dean Stark trap water is eliminated and the alcohol having the structure: ##STR77## is recovered. The reaction temperature gradually rises to 125° C. as water is eliminated and the total reaction time is 10 hours. The total amount of water evolved is 252.0 grams. When the water of reaction ceases to evolve, the reaction mass is cooled to 70° C. Once all of the water is removed the compound having the structure: ##STR78## as recovered weighs 1227.0 grams. This material having the structure: ##STR79## is used for Examples II, III, IV and V, infra.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>N1C=CC=CC=1>[C:1]([NH:5][CH2:6][CH:7]([O:20][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1)[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)NCC(O)COc1cccc2c1CC(=O)N2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NCC(COc1cccc2c1CC(=O)N2)OC(=O)c1cccnc1
Reaction time: 96 h

Procedure:
1 g of 4-(3-tert-butylamino-2-hydroxypropoxy)oxindole, 20 cc of chloroform, 10 cc of pyridine and 0.713 g of nicotinoyl chloride are allowed to stand at room temperature for 4 days, the mixture is then concentrated by evaporation as carefully as possible at reduced pressure and the residue is taken up in water. The reaction mixture is rendered alkaline with a 10% ammonia solution, is extracted with methylene chloride, and subsequently an excess of 2 N hydrochloric acid in ethanol is added. The solvent and excess hydrochloric acid are carefully removed by evaporation at reduced pressure and the dihydrochloride of the title compound is crystallized from ethanol, needle druses. M.P. 215°-218° .
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH2:49][NH:50][C:51]1[N:56]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:54]=[C:53]([NH:64][CH2:65][CH2:66][NH:67][C:68](=[O:70])[CH3:69])[C:52]=1[CH3:71]>CN1C(=O)CCC1>[C:68]([NH:67][CH2:66][CH2:65][NH:64][C:53]1[N:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:56]=[C:51]([NH:50][CH2:49][CH2:48][NH:47][C:11]([C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])[C:52]=1[CH3:71])(=[O:70])[CH3:69]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CC(=O)NCCNc1nc(-c2ccc(Cl)cc2)nc(NCCN)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)NCCNc1nc(-c2ccc(Cl)cc2)nc(NCCNC(=O)c2cc3ccccc3cn2)c1C
Reaction time: 12 h

Procedure:
A solution of 3-isoquinoline carboxylic acid (60 μl of a 0.3M solution in NMP), HATU (60 μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 20 min. N-{2-[6-(2-Aminoethylamino)-2-(4-chlorophenyl)-5-methylpyrimidin-4-ylamino]-ethyl}acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 12 hrs. Purification via ion exchange silica (SCX) yields the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:19][C:20](=[O:23])[CH2:21][Cl:22])([CH2:14][O:15]COC)[CH2:9][O:10]COC)[CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C(S)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:19][C:20](=[O:23])[CH2:21][Cl:22])([CH2:14][OH:15])[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COCOCC(COCOC)(NC(=O)CCl)c1cccc(Br)n1
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Product: O=C(CCl)NC(CO)(CO)c1cccc(Br)n1
Reaction time: 0.17 h

Procedure:
To a solution of N-[1-(6-bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethyl]-2-chloro-acetamide (9.0 g, 21.861 mmol) in ethanethiol (30 ml) and BF3.Et2O (9.3 g, 141.93 mmol) was added at 0° C. and stirred for 10 min. Stirring was continued for 3 h at rt. Reaction mixture was quenched with saturated NaHCO3 solution and the product formed was extracted with ethyl acetate. Organic layer was separated and washed with brine solution, followed by drying over anhydrous Na2SO4. Organic layer was concentrated under reduced pressure and purified by column chromatography using 2% methanol in chloroform to obtain title compound as a brown liquid. Yield=5.5 g (77%). TLC (10% methanol in chloroform) Rf=0.51; LCMS: RtH8=0.916, [M+1]=322.9 and 324.8; HPLC RtH9=5.931 min (89%); 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.56 (t, 1H), 7.42-7.39 (m, 2H), 4.38 (s, 2H), 4.09-4.07 (m, 4H), 3.95 (d, 2H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:23]([O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[CH2:23]([O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([Cl:12])=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:11])[N:39]=2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCOc1ccc(C#N)cc1
Reactant: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCOc1ccc(-c2nc(-c3c(Cl)cccc3Cl)nn2C)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
A mixture of 1.10 g of N-methyl-N-phenylsulfonyl-2,6-dichlorobenzohydrazonoyl chloride, 0.70 g of 4-decyloxybenzonitrile, 0.4 g of anhydrous aluminium chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.40 g of the given compound (melting point: 60.0°-64.0° C.).