Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[CH:3]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[CH3:10])C(F)(F)F.CC(=O)C(=O)CC>>[F:11][C:9]([F:12])([C:8]([F:14])([F:13])[CH2:3][CH3:2])[CH3:10]
Reactant: CC(F)(F)C(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: CCC(=O)C(C)=O
Product: CCC(F)(F)C(C)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,3,3,4,4-heptafluoropentane may be prepared by fluorinating commercially available 2,3-pentanedione to form 2,2,3,3-tetrafluoropentane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-pentene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-pentene to form 2-trifluoromethyl-1,3,3,4,4-pentafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoro-1-pentene which may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,1,3,3,4,4-heptafluoropentane.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:25][C:9]2=[CH:10][N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])C>C1COCC1.CO.O>[CH:20]1([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[CH:13]=[C:8]4[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:25][C:9]4=[CH:10][N:11]=3)[CH2:19][CH2:18]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cc2cc(N3CCN(C4CCCC4)CC3)ncc2[nH]1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc(N3CCN(C4CCCC4)CC3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A mixture of 0.65 g (1.9 mmol) 5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester and LiOHxH2O in THF/methanol/water was stirred at room temperature for 16 h. After evaporation of all volatiles the residue was taken up in water and HCl conc. was added. After evaporation the residue was treated with diethyl ether filtered, washed again with diethyl ether and dried to yield 0.46 g (69%) of the title compound as orange solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:11]([Cl:12])=[C:10]2[C:6]([CH2:7][C:8]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:13])=[CH:5][C:4]=1[OH:21].I[CH2:23][CH2:24][OH:25]>C(O)CC>[Cl:2][C:3]1[C:11]([Cl:12])=[C:10]2[C:6]([CH2:7][C:8]([CH3:20])([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:13])=[CH:5][C:4]=1[O:21][CH2:23][CH2:24][OH:25]
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: OCCI
Agent: [Na]
Solvent: CCCO
Product: CC1(c2ccccc2)Cc2cc(OCCO)c(Cl)c(Cl)c2C1=O
Yield: 45 %

Procedure:
To a solution of sodium (1.76 g., 0.076 g. atom) in 1-propanol (250 ml.) is added 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone (23.5 g., 0.076 mole) and 2-iodoethanol (14.5 g., 0.085 mole). The reaction mixture is refluxed 18 hours then evaporated at reduced pressure to give 12.0 g of 2-(6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)ethanol which melts at 188°-90° C. after recrystallization from ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:25]#[N:26].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CS(C)=O.CCOC(C)=O>[C:25]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)=[N:7][C:2]=1[NH:30][CH:27]1[CH2:29][CH2:28]1)#[N:26]
Reactant: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1)c1ccccc1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(NC3CC3)n2)C1)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(R)-3-(1-(6-Chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (513, 100 mg) was dissolved in 4 mL DMSO in a sealed tube. To it was added cyclopropylamine (210 μL, 3 mmol) and the mixture was stirred in 70° C. bath for 16 hours. It was diluted with 60 mL EtOAc, washed with water ×2, concentrated in vacuo to afford crude (R)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (514). It was dissolved in 4 mL MeOH and 2 mL DMSO. To it were added one NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 45 min, diluted with 10 mL MeCN, stirred for 5 min, concentrated on rotavap. The residue was treated with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide (515) as HCl salt (74 mg, 67% yield). LC-MS (ESI): m/z (M+1) 410.3. UV: λ=283, 317, 369 nm.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:33][CH2:34][CH2:35][CH3:36])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4].CC(C)=O>C(O)C>[C:29]([O:28][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:9]2[C:10]([C:11]#[N:12])=[C:6]([CH:3]([OH:5])[CH3:4])[N:7]=[C:8]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:15][CH:16]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCCc1nc(C(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
0.098 g of sodium borohydride was added to a solution of 1.18 g of 4-acetyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butylimidazole-5-carbonitrile [prepared as described in step (a) above] in 30 ml of ethanol, and the resulting mixture was stirred at room temperature for 1 hour. The excess sodium borohydride was decomposed by adding acetone, and then the reaction mixture was concentrated by evaporation under reduced pressure. The residue was diluted with an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was dried and concentrated by evaporation under reduced pressure. The oily residue was purified by column chromatography through silica gel, using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to afford 1.18 g of the title compound as a viscous oil.
Reaction SMILES: CCCCC.[H-].[Na+].[CH3:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:21]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][N:19]=[C:18]([S:26][CH3:27])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][CH:28]([NH:31][C:32]([NH:25][S:22]([C:21]1[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=2)=[N:17][C:18]([S:26][CH3:27])=[N:19][CH:20]=1)(=[O:23])=[O:24])=[O:33])[CH3:30]
Reactant: CSc1ncc(S(N)(=O)=O)c(Nc2cccc(C)c2)n1
Reactant: CC(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CSc1ncc(S(=O)(=O)NC(=O)NC(C)C)c(Nc2cccc(C)c2)n1
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
Pentane washed sodium hydride (3.99 mmol, 1.05 eq) was suspended in THF (50 mL), and 4-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinesulfonamide (1.18 g, 3.90 mm) was added slowly as a solid. The mixture was stirred for 90 minutes and isopropyl isocyanate (0.39 mL, 3.99 mmol, 1.05 eq) was added. After stirring 45 minutes an additional 0.1 mL of isopropyl isocyanate was added to complete the reaction. The THF was removed under reduced pressure and the residue was dissolved in dilute sodium hydroxide. Acetic acid was added until a pH of 4 and the aqueous solution was extracted with four 50 mL portions of ethyl acetate. The organic portions were combined, dried (Na2SO4), filtered and the solvent removed under reduced pressure to yield 1.61 g of crude solid. The crude solid was crystallized from ethanol and water to yield 1.21 g (3.06 mmoles, 80%) of white crystals, m.p. 160°-160.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:11]([CH:13]=O)=O.O.BrCCBr.O.NN.[OH-].[K+]>C(O)C.CN(C)C=O>[NH:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:13][CH2:11][NH:1][CH2:2][CH2:3]1
Reactant: O=CC=O
Reactant: NCCNCCNCCN
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: BrCCBr
Product: C1CNCCNCCNCCN1
Reaction time: 20 h

Procedure:
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 l of ethanol and mixed at room temperature with 39 ml of 40% glyoxal in water (0.342 mol). After 20 hours of stirring, the solvent is distilled off in a vacuum, and an orange-colored oil is obtained, which then is taken up in 400 ml of dimethylformamide and mixed with 88.5 ml (192.8 g=1.026 mol) of 1,2-dibromoethane. After 6 hours of stirring at 40° C., it is concentrated by evaporation in a vacuum, the residue is taken up in 400 ml of ethanol and acidified to pH=3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g=3.42 mol) of hydrazine hydrate is added to this reaction solution at room temperature, and it is heated under reflux for 30 hours. The reaction solution is set at pH=13 with solid potassium hydroxide. The reaction solution is subsequently concentrated by evaporation in a vacuum, taken up once more in 100 ml of ethanol, and the solvent is removed again in a vacuum. The residue is mixed with 25 g of activated carbon and 150 ml of formaldehyde diethylacetal, and it is heated under reflux for some time before the hot solution is filtered through a membrane. After the solution is cooled, the product is isolated by filtration.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[N:3]=[C:4]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ccsc2n1
Reactant: CNc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(c1ccccc1)c1nc(N(C)c2ccccc2)c2ccsc2n1

Procedure:
2,4-Dichlorothieno[2,3-d]pyrimidine (2 g, 0.00975 mol) and N-methylaniline (5 ml) were heated in an oil bath at 150° for 2 hours. The reaction mixture was dissolved in chloroform (200 ml) and extracted with 2N hydrochloric acid (3×100 ml). The chloroform solution was then washed with sodium carbonate solution, dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was purified by chromatography using dichloromethane as eluant. The solid obtained was recrystallized from ether/petroleum ether (b.p. 40°-60°) to give the title compound, (1.2 g) m.p. 85°-87°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:32])[F:33])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Temperature: 0 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
To an ice cold solution of (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (100 mg, 455 μmol), 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol (111 mg, 455 μmol) and tributylphosphine (160 μl, 546 μmol) in tetrahydrofuran (10 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (94 mg, 546 μmol). The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to obtain 65 mg (150 μmol, 32%) of the title compound as colorless oil.
Reaction SMILES: [OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:5]
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)[C@@](C)(O)c1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2S)-2-hydroxy-2-phenylpropanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ES I) m/z: 407.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].C[Si](C)(Cl)Cl.[Cl-].[NH4+]>CCOCC.[Cu](C#N)C#N>[CH2:3]([C:4]1[CH2:10][C:9]2[C:6]([CH:5]=1)=[C:2]([C:3]1[C:3]3[C:2]([C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH:4]=1)=[CH:1][CH:6]=[CH:5][CH:4]=3)[CH:1]=[CH:7][CH:8]=2)[CH2:2][CH3:1]
Reactant: CCCCCC
Reactant: [Li]CCCC
Agent: N#C[Cu]C#N
Agent: C[Si](C)(Cl)Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CCCC1=Cc2c(cccc2-c2cc3ccccc3c3ccccc23)C1
Yield: 54 %

Procedure:
A 300-ml four-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 6.20 g (18.5 mmol) of 2-n-propyl-4-(9-phenantolyl)indene, 120 ml of dry ether and 50 mg of copper cyanide. To the mixture was added dropwise 12.5 ml (20.4 mmol) of a hexane solution containing 1.63M n-butyl lithium while cooling with ice bath. After the addition was completed, the mixture was stirred under reflux for 1.5 hours. Then, to the resulting mixture was added dropwise a solution containing 1.34 ml (11.1 mmol) of dimethyldichlorosilan dissolved in 10 ml of dry ether. After the addition was completed, the mixture was stirred overnight at room temperature. Then, the reaction mixture was poured onto 200 ml of a saturated aqueous solution of ammonium chloride. After the filtration, the filtrate was extracted with 100 ml of ether three times. The organic phase was washed with 200 ml of a saturated NaCl aq. and dried over anhydrous MgSO4. The solvent was evaporated to give a yellow-white powder. The powder thus obtained was purified with silica gel chromatography to give 3.80 g of the desired product as a yellow-white powder (yield: 54%).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N.C([O:17]CC)C>>[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:17]
Reactant: N#Cc1cccc(OC(F)(F)F)c1
Reactant: CCOCC
Agent: Cl
Product: O=Cc1cccc(OC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
103 g. (0.544 mol) of stannous chloride and 400 ml of diethyl ether are introduced into a one litre three-necked flask equipped with a condenser, a mechanical stirrer and a gas bubbler tube. This mixture is cooled and saturated with hydrogen chloride gas until the stannous chloride is completely dissolved. A solution of 72.7g. (0.388 mol) of 3-trifluoromethoxy-benzonitrile in 75 ml. of anhydrous diethyl ether is added dropwise but fastly via the dropping funnel, while the mixture is cooled with ice-water. The mixture is allowed overnight, then the aldehyde is steam distilled. The distillate is extracted several times with diethyl ether and the extracts are combined. 250 ml. of a solution of sodium bisulphite (d=1.32-1.33) are added to the extracts and allowed overnight. The bisulfite compound is filtered off, washed with a small quantity of ice-water and then with diethyl ether. The compound is introduced into a one litre flask which contains solution of 60 g. of potassium carbonate in 250 ml. of water. The mixture is heated at 100°C so as to decompose the bisulfite compound and to steam distil the aldehyde as it is formed. The distillate is extracted several times with diethyl ether. The combined ether phases are dried over sodium sulphate and filtered and the solvent is evaporated. 32g. (44% yield) of 3-trifluoromethoxy-benzaldehyde are obtained as a colourless oil.
Reaction SMILES: CN(C)C=O.[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH2:21])=[N:13]1)[CH3:7].Br.Br[CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[N:13]1)[CH3:23]
Reactant: CCN(CC)CCCn1nc(N)c2ccccc21
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 8.1 g of 1-(3-diethylaminopropyl)-3-amino-indazole obtained by the same method as described in Example 5, 9.0 g of 3-bromopropyldiethylamine hydrobromide and 7.9 g of anhydrous potassium carbonate. The mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 6.99 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 54%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N+:28]([C:31]1[C:32]([NH2:46])=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)([O-:30])=[O:29]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:36]=[C:31]([N+:28]([O-:30])=[O:29])[C:32]([NH2:46])=[N:33][CH:34]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2cnc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)c([N+](=O)[O-])c4)nc3s2)CC1
Yield: 16.8 %

Procedure:
4-(2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine (100 mg, 0.2 mmol) was reacted with 3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.24 g, 0.9 mmol) according to General Procedure Suzuki to afford 360 (18 mg) following reverse phase HPLC purification. MS (Q1) 535 (M)+
Reaction SMILES: ClCCN.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22]C2CCN(CCN=C=S)CC2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH2:22])=[CH:10][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Agent: NCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2ccccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.2 parts of 2-chloroethanamine, 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 2.2 parts of sodium carbonate and 135 parts of tetrahydrofuran was stirred for 3 hours at room temperature. The mixture was heated to reflux and stirring was continued overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized twice from acetonitrile, yielding 1 part of N-[1-[2-[4,5-dihydro-2-thiazolyl)amino]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine; mp. 147.6° C. (compound 99).
Reaction SMILES: C(OC(=O)[CH:5]([C:16]#[N:17])[C:6]1[CH:7]=[N:8][C:9]([C:12](F)(F)F)=N[CH:11]=1)C.BrCC1CC1.[Na+].[I-].C1COCC1.[NH4+].[Cl-:32]>O1CCOCC1>[Cl:32][C:12]1[CH:11]=[C:6]([CH2:5][C:16]#[N:17])[CH:7]=[N:8][CH:9]=1
Reactant: [Cl-]
Reactant: CCOC(=O)C(C#N)c1cnc(C(F)(F)F)nc1
Agent: BrCC1CC1
Agent: [I-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#CCc1cncc(Cl)c1
Temperature: 105 °C
Yield: 44.6 %

Procedure:
A mixture of cyano-(2-trifluoromethyl-pyrimidin-5-yl)-acetic acid ethyl ester (240 mg, 0.93 mmol), bromomethyl cyclopropane (375 mg, 2.78 mmol) and NaI (139 mg, 0.93 mmol) in dry dioxane (2 mL) was degassed and ButOK in THF (1.11 mL, 1.11 mmol) was added at room temperature. The resulting mixture was heated to 100-110° C. for 24 h. Saturated NH4Cl solution was added to quench the reaction at 0° C. and extracted with EtOAc (5 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc=20:1˜5:1) to give the title compound (100 mg, yield: 44.6%). 1H NMR (CDCl3 400 MHz): δ8.94 (s, 2H), 4.09-4.01 (m, 1H), 2.05-1.95 (m, 111), 1.93-1.80 (m, 1H), 0.91-0.79 (m, 1H), 0.69-0.60 (m, 2H), 0.25-0.14 (m, 2H).
Reaction SMILES: [C:1]([CH:3]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1)C(OC)=O)#[N:2].[Cl-].[Na+]>CS(C)=O.O>[Cl:14][C:13]1[C:8]([CH2:3][C:1]#[N:2])=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: COC(=O)C(C#N)c1ncc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ncc(Cl)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
Methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)acetate (120 mg, 0.490 mmol) was diluted with DMSO (1 mL) and water (40 uL) followed by the addition of sodium chloride (14.3 mg, 0.245 mmol). The reaction was heated to 130° C. and stirred for 3 hours. The reaction was allowed to cool, loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield the desired compound (70 mg, 0.374 mmol, 76.4% yield).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:27]([NH:26][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:28])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(SC)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-trifluoromethyl-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) and the corresponding isocyanate using the procedure described for compound (10).