Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8]CC)=[O:7])C.[CH2:13]([O:15][CH:16]([O:20][CH2:21][CH3:22])[CH2:17][NH:18][NH2:19])[CH3:14]>C(O)C.O>[CH2:13]([O:15][CH:16]([O:20][CH2:21][CH3:22])[CH2:17][N:18]1[C:11]([NH2:12])=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=[N:19]1)[CH3:14]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCOC(CNN)OCC
Solvent: CCO
Solvent: O
Product: CCOC(Cn1ncc(C(=O)O)c1N)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 27.6 %

Procedure:
To a suspension of ethyl ethoxymethylenecyanoacetate (21.7 g) in ethanol (65 ml) was added dropwise a solution of hydrazinoacetaldehyde diethyl acetal (19 g) in water (19 ml) under ice-cooling. The mixture was stirred at 80° C. for 1.5 hours and evaporated to remove ethanol. To the residue was 4N sodium hydroxide (64 ml), and the mixture was refluxed for 1 hour. The mixture was adjusted to pH 3.5 with concentrated hydrochloric acid at 10°-20° C., and the resulting precipitate was collected by filtration to give 1-(2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (8.60 g). IR (Nujol) : 3460, 3360, 1645, 1620, 1545 cm-1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C([Li])CCC.[C:21]([N:40]1[CH:44]=[C:43]([CH:45]=[O:46])[N:42]=[CH:41]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[OH:46][CH:45]([C:43]1[N:42]=[CH:41][N:40]([C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:44]=1)[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Under nitrogen atmosphere, 5.8 liters of THF was added to 105.6 g (0.40 mol, 1.2 eq) of 6-bromo-N-methyl-2-naphtamide, the mixture was warmed to 50° C. to dissolve it. 500 mL (0.50 mol, 2.4 eq) of a 1.6 M solution of n-butyllithium in hexane was added dropwise at −65° C. or lower over 35 minutes. The mixture was stirred at −65° C. for 1 hour. A solution of 112.7 g (0.33 mol) of 1-trityl-4-formyl-1H-imidazole in 810 mL of THF was added dropwise at −65° C. or lower over 40 minutes. The mixture was stirred at −65° C. for 2 hours. 1.5 Liters of an aqueous saturated ammonium chloride solution was added dropwise at −20° C. or lower, and the mixture was warmed to 30° C. After separation of the layers, the organic layer was washed with 1.5 liters of an aqueous saturated sodium chloride solution two times. After concentration under reduced pressure, 1 liter of ethyl acetate was added to the residue, and the mixture was stirred at 25° C. for 3 hours. Crystals were filtered, and washed with ethyl acetate. Vacuum drying (50° C.) to a constant weight afforded 87.9 g of 6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (yield 50%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][N:17]=[C:18]=[S:19].CCOC(C)=O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:18]([NH:17][CH3:16])=[S:19])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CN=C=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=S)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 1-Boc-4-aminomethylpiperidine (642 mg, 3 mmol) in THF (8 ml), methyl isothiocyanate (241 mg, 3.3 mmol) was added and the mixture was stirred at room temperature overnight. Upon completion of the reaction, purification was performed by silica gel column chromatography (Hex/AcOEt=1/4) to obtain 4-({[(methylamino)thioxomethyl]amino}methyl)piperidine carboxylic acid tert-butyl ester. The compound was identified by LC-MS.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[OH-].[NH4+:14]>CN(C=O)C.O>[NH2:14][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([C:11]#[N:12])[C:2]=1[F:1]
Reactant: N#Cc1nc(F)c(F)c(F)c1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(F)c(F)c(N)c1F
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 3,4,5,6-tetrafluoro-2-cyanopyridine in DMF (75 mL) at 0C was slowly added concentrated ammonium hydroxide (15 mL). The reaction was stirred and additional 15 min and the solution was diluted with water (150 mL). The solid was collected and air dried to give 4-amino-3,5,6-trifluoro-2-cyanopyridine (25.5 g, 0.16 mol, 92%); mp 291-30 C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([CH3:31])[CH2:10][C@H:11]([O:29][CH3:30])[C@@H:12]([OH:28])[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.O([Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])S(C(F)(F)F)(=O)=O>C(=O)(O)[O-].[Na+]>[C:1]([O:7][CH2:8][C@H:9]([CH3:31])[CH2:10][C@H:11]([O:29][CH3:30])[C@@H:12]([O:28][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](O)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Product: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
Alcohol 24 (2.98 g, 6.48 mmol) was dissolved in 50 ml of methylene chlorideat 25° C. and 2,6-lutidine (1.51 ml, 2.0 equiv) was added. t-Butyldimethylsilyl triflate (2.23 ml, 1.5 equiv) was added and the mixture was stirred at 25° C. for 10-15 min. The solution was poured in 40 ml of saturated aqueous sodium bicarbonate solution and extracted with 2×200 ml of methylene chloride. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give4.0 g of the bis-t-butyldimethylsilyl ether 25 as an oil. This material washomogeneous by 1H and 13C NMR and was used directly in the subsequent transformation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6](Cl)[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1.[Na].[CH2:20]([OH:22])[CH3:21]>>[Cl:1][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([O:22][CH2:20][CH3:21])[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C)N=C1Cl
Reactant: CCO
Agent: [Na]
Product: CCOC1=C(C2=NCCN2)C(Cl)=NC(C)N1N

Procedure:
3.0 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are introduced at room temperature into a solution of 0.5 g sodium in 10 ml ethanol. Subsequently, the solution is heated for 30 minutes to 75° C., filtered, the filtrate is concentrated, the residue is placed in ice water, and the crystals are vacuum dried. After recrystallization from nitromethane, 1.2 g (45%) of 4-chloro-6-ethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine, melting point 221° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH:10]([OH:30])[CH:11]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])[C:12](OC)=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:31][NH2:32]>CO>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH:10]([OH:30])[CH:11]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])[C:12]([NH:32][CH3:31])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CSc1cccc(F)c1
Solvent: CO
Product: CNC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CSc1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
760 mg (about 1.5 mmol) of crude product from step 1.5 were dissolved in methanol. With gentle cooling, gaseous methylamine was then introduced for 30 min. The mixture was stirred at RT for 15 h. The solvents were then removed, the residue was stirred with MTBE and the precipitate was filtered off with suction. This gave 416 mg (62% of theory over 2 steps) of the title compound (4:1 diastereomer mixture) as a colorless solid of m.p. 172° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][N:4](C(OC(C)(C)C)=O)[CH:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([C:16](=[O:19])[NH:17][CH3:18])=[CH:15][C:7]=2[CH2:6]1.[ClH:35]>C(OCC)(=O)C>[ClH:35].[OH:1][C@H:2]([CH2:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([C:16](=[O:19])[NH:17][CH3:18])=[CH:15][C:7]=2[CH2:6]1
Reactant: CNC(=O)c1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2

Procedure:
A solution of N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-(3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (108 mg) in ethyl acetate (1 ml) was treated with 4N hydrogen chloride in ethyl acetate solution (0.58 ml) overnight. The mixture was evaporated in vacuo and triturated in diisopropyl ether, and the precipitated powder was collected by filtration to afford 6-[(2S)-2-hydroxy-3-phenoxypropyl]amino-3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride (86 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>COCCO>[CH2:11]([NH:18][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Clc1ncnc2ccsc12
Solvent: COCCO
Product: c1ccc(CNc2ncnc3ccsc23)cc1
Yield: 26.2 %

Procedure:
As described in the previous experiment 4-chlorothieno[3,2-d]pyrimidine (100 mg, 0.586 mmol) and benzylamine (710 μL, 0.645 mmol) in 2-methoxyethanol (2 mL) yields 4-benzylaminothieno[3,2-d]pyrimidine (37 mg, 26%). 1H NMR (DMSO) δ 8.42 (1H, s), 8.12 (1H, d, J=5.5 Hz), 7.39 (1H, d, J=5.3 Hz), 7.40-7.30 (4H, m), 7.24 (1H, t, J=6.8 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C.C(N(C(C)C)C(C)C)C>CO>[NH2:19][C:18]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=2[CH3:10])[N:9]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1c(Br)cccc1NN
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(3-Bromo-2-methylphenyl)hydrazine (CAS no. 459817-67-5) (10 g, 49.74 mmol) was suspended in MeOH (100 mL) under nitrogen at 0° C. 2-(Ethoxymethylene)malononitrile (6.07 g, 49.74 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 2 hours. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. No reaction. The starting material was NMRed and found to be a salt, so N-ethyl-N-isopropylpropan-2-amine (17.33 mL, 99.47 mmol) was added and stirred for a further 16 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc, and washed sequentially with water ×2 and saturated brine. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product, 5-amino-1-(3-bromo-2-methylphenyl)-1H-pyrazole-4-carbonitrile (12.60 g, 91%). m/z (ES+) (M+H)+=279.25; HPLC tR=1.95 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:34]=[C:33]5[C:28]([CH:29]=[CH:30][C:31](=[O:35])[O:32]5)=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5ccc(=O)oc5c4)ncnc32)CC1
Yield: 15.3 %

Procedure:
4-[4-(2-Oxo-2H-chromen-7-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (6.4 mg, 16%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.09 mmol) with 7-hydroxy-coumarin (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 15 mg, 0.09 mmol) in the presence of potassium carbonate (27 mg, 0.195 mmol). Mass spectrum MH+=464.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1.OP([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][CH2:6][C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(CO)o1
Reactant: CC(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C=O)o1
Temperature: 20 °C

Procedure:
10.05 cm3 of acetyl chloride is added at 5° C. to a solution containing 16.2 g of 5-(hydroxy methyl) 2-furan-carboxaldehyde and 200 cm3 of methylene chloride. Then 11.4 cm3 of pyridine and 50 cm3 of methylene chloride are added. The reaction mixture is maintained under agitation for 3 hours at 20° C. It is then treated with an aqueous solution of sodium acid phosphate and extracted with methylene chloride, followed by drying and concentrating. After chromatography on silica eluting with a hexane--ethyl acetate mixture (7-3), 19.35 g of desired product is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19](O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([N:4]2[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nn(C2CCN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.5 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-pyrazole (3.0 g, 23.6 mmol, 1.00 eq), tert-butyl-3-hydroxypyrrolidine-1-carboxylate (4.42 g, 23.6 mmol, 1.00 eq), and triphenylphosphine (6.19 g, 23.6 mmol, 1.00 eq) in THF (60 mL) was added a solution of diethyl azodicarboxylate (4.34 mL, 23.6 mmol, 1.00 eq) in THF (10 mL) in a drop-wise manner over 30 min. The reaction mixture was allowed to stir at ambient temperature for 20 hr and then concentrated. The crude reaction mixture was purified via repeated flash chromatography on silica gel eluting with a gradient of 0-35% EtOAc in heptane to give the title compound (2.48 g, 35% yield) as a colorless oil that was the early eluting of two structural isomers. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1 H) 4.80 (quin, J=5.7 Hz, 1 H) 3.83 (dd, J=6.0, 12.0 Hz, 1 H) 3.79-3.45 (m, 3 H) 2.52 (s, 3 H) 2.38 (q, J=7.0 Hz, 2 H) 1.46 (s, 9 H). m/z (APCI+) for C13H21N4O4 197.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: NC1CCCCC1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C=NC2CCCCC2)c([N+](=O)[O-])cc1OC
Yield: 80.4 %

Procedure:
A suspension of 42.2 g (0.2 mole) of 6-nitroveratraldehyde, 19.8 g (0.2 mole) cyclohexylamine, 1.0 ml. glacial acetic acid, and 1.25 l. ethanol was stirred and refluxed for 5 min., cooled, and filtered. The solid was washed with 100 ml. cold ethanol and air dried to give 47.0 g (80%) of the product, m.p. 160°-161°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>>[CH2:26]([O:25][C:23]([CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Product: CCOC(=O)COc1ccc(Nc2cc(Nc3cccc(C)c3)ncn2)cc1
Yield: 33.1 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-(3'-methylanilino)pyrimidine (1.0 g) was reacted with ethyl 4-aminophenoxyacetate (1.0 g). The product so obtained was chromatographed on silica to give 4-[4'-(ethoxycarbonylmethoxy)anilino]6-(3'-methylanilino)pyrimidine (0.57 g).
Reaction SMILES: [CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2csc(C3CCC3)n2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(/C=C/c2csc(C3CCC3)n2)c1
Temperature: 0 °C
Yield: 111.7 %

Procedure:
A mixture of 0.3 g of (E)-2-cyclobutyl-4-[2-(3-nitrophenyl)ethenyl]thiazole, 0.9 g of tin(II) chloride dihydrate and 50 ml of ethyl alcohol was heated to reflux for 16 hr. The mixture was then diluted with ice water and basified with an excess of 3N sodium hydroxide. This mixture was extracted with methylene chloride and the combined extracts were washed with water followed with brine and then dried (MgSO4). Condensation in vacuo yielded 0.3 g of (E)-3-[2-[2-Cyclobutyl-4-thiazolyl]ethenyl]phenylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:10](=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH3:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:12][S:13]([C:15]([CH3:16])([CH3:18])[CH3:17])=[O:14])[CH3:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccc(C#N)c(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(C#N)c(Br)c1
Reaction time: 0.17 h

Procedure:
To a solution of 38-1 (500 mg, 1.5 mmol) in THF (4 mL) at −78 C was added L-Selectride (3.1 mL, 3.1 mmol, 1M). After 10 minutes, the reaction was diluted in EtOAc, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase chromatography (1-100%, 0.1% TFA in H2O/Acetonitrile) gave desired product. MS (M+H)+: observed=329.0/331.0, calculated=329.3/331.3.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=2)[CH:4]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].Cl>>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:23])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example C.14) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 488.9 [(M−H)−]; mp 270° C.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>>[F:25][C:26]1[N:27]=[CH:28][C:29]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:30][C:31]=1[CH3:32]
Reactant: Cc1cc(B(O)O)cnc1F
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: Cc1cc(-c2ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nn23)cnc1F

Procedure:
[7-(6-Fluoro-5-methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 2-fluoro-3-methylpyridine-5-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (66 mg, 56%). m.p.=210° C.; LCMS (m/e) 418 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.61-8.53 (m, 2H), 7.52-7.45 (m, 2H), 6.99-6.92 (m, 3H), 6.82 (d, 1H, J=4.8 Hz), 6.66 (bs, 1H), 3.22-3.16 (m, 4H), 2.63-2.57 (m, 4H), 2.37 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccc(Nc2ccccc2CC(=O)O)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-nitro-4-methoxyaniline to yield 2-[(2-nitro-4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[O:27][CH2:28][O:29][C:21]=12>>[Cl:16][CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:17][CH3:18])[N:5]=[CH:4][N:3]=[C:2]2[NH:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[O:27][CH2:28][O:29][C:21]=12
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: COc1cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c2cc1OCCCCl
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 58% yield; NMR Spectrum: (CDCl3) 2.4 (m, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.15 (s, 2H), 7.05 (s, 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.75 (s, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 423 and 425.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=[C:7]1[C:5]1[N:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:23]=[CH:24][CH:25]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Reactant: NNc1ccnc2ccccc12
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=391.1 (M+H)+