Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])/[CH:11]=[CH:12]/[C:13]([O:15]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])/[CH:11]=[CH:12]/[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)/C=C/C(=O)c1ccc(OC)c(Cl)c1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)/C=C/C(=O)c2ccccc2)cc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Into a 200 ml four-neck flask were added 10 g (0.038 mol) of ethyl (E)-4-(3-chloro-4-methoxyphenyl)-4-oxo-2-butenoate obtained in Example 3 and 50 ml of tetrahydrofuran under a nitrogen atmosphere, and 22.5 ml (0.045 mol) of a tetrahydrofuran solution of 32% phenylmagnesium bromide was slowly added dropwise so as to maintain inner temperature at 10° C. or lower. Then, after 1 hour of stirring at room temperature, the whole was again cooled and 50 ml of a 5% ammonium chloride aqueous solution was added thereto. After liquid separation, the resulting organic layer was washed with 50 ml of a 10% sodium bicarbonate aqueous solution and then with 50 ml of water. After the solvent was removed by evaporation under reduced pressure, the residue was crystallized from 10 ml of ethanol to obtain 8.9 g (yield 78.0%) of the aimed compound. As a result of HPLC analysis, the purity was found to be 99.3%.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClCC(OC(=O)CCl)=O.[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClC(Cl)C>[CH3:26][O:25][C:19]1[CH:24]=[CH:23][C:22]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:21][CH:20]=1
Reactant: COc1ccccc1
Reactant: CCCCCCC(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: CCCCCCC(=O)c1ccc(OC)cc1
Yield: 84 %

Procedure:
In 40 ml of dichloroethane were dissolved 6.51 g (0.05 mole) of heptanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 7.57 g (0.07 mole) of anisole and 0.9 g of boron trifluoride-acetic acid complex and the resulting mixture was then stirred at refluxing for 8 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure to obtain 9.25 g of 4-methoxy-1-heptanoyl-benzene.
Reaction SMILES: Cl.C(OCC)C.C(OC([N:14]([CH:25]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)[CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1)=O)(C)(C)C>ClCCl>[F:31][C:28]([F:29])([F:30])[CH2:27][CH2:26][CH:25]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1)[C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Reaction time: 18 h
Yield: 73.2 %

Procedure:
A 2M solution of HCl in diethyl ether (1 mL, 2 mmol) was added to a room temperature solution of methyl 6-(tert-butoxycarbonyl(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)amino)nicotinate (30 mg, 0.051 mmol) in 1 mL dichloromethane. After 18 h, the solution was concentrated and the residue redissolved in 2 mL trifluoroacetic acid. After 2 h, the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give methyl 6-(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (18 mg, 73%) as a colorless film. 1H NMR (400 MHz, CDCl3) 8.72-8.74 (m, 1H), 7.94 (dd, J=8 Hz, 2.5 Hz, 2H), 7.61-7.70 (m, 4H), 7.57 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 6.29 (d, J=8.8 Hz, 1H), 5.40 (d, J=7.6 Hz, 1H), 4.90-5.01 (m, 1H), 3.83 (s, 3H), 2.06-2.36 (m, 4H).
Reaction SMILES: C(OCC[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH3:16])=[N:8]1)(=O)C.C1C(=O)N([Br:24])C(=O)C1.[CH3:25][CH2:26][O:27][C:28]([CH3:30])=[O:29]>C(Cl)(Cl)(Cl)Cl>[CH2:26]([O:27][C:28](=[O:29])[CH2:30][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH2:16][Br:24])=[N:8]1)[CH3:25]
Reactant: CCOC(C)=O
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCn1nc(C)c2cccnc21
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1nc(CBr)c2cccnc21

Procedure:
A mixture of (3-methyl-pyrazolo[3,4-b]pyridine-1-yl)ethyl acetate (2.5 mmol, 1 eq.), NBS (3.0 mmol, 1.2 eq.), and benzoly peroxide (0.05 mmol, 0.02 eq.) in 10 mL of CCl4 was refluxed for 1.5 h. The resultant mixture was cooled to rt, and diluted with 500 mL of EtOAc. The resultant solution was then washed with 100 mL of sat. sodium bicarbonate aqueous solution, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (20% EtOAc in hexane to 35% EtOAc in hexane) to provide 450.2 mg of the desired product: HPLC retention time=2.50 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 0% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=298.0. found=298.3.
Reaction SMILES: O=O.[CH3:3]C(C)([O-])C.[K+].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].CI>C1COCC1.O>[CH3:3][CH:10]([C:11](=[O:12])[CH3:13])[C:9]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: O=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CCOC(=O)C(C)C(C)=O
Reaction time: 1 h
Yield: 70 %

Procedure:
Under nitrogen atmosphere free of water and oxygen, to a three-necked flask equipped with a dropping funnel were successively added 0.15 mol of potassium tert-butoxide and 150 ml of THF, then stirrer was started. 0.12 Mol of ethyl acetoacetate was slowly dropped to the reactor cooled in an ice-water bath. Upon completion of the dropping, the reaction was continued at room temperature for further 1 hr. Then 0.18 mol of methyl iodide was slowly dropped at room temperature, and then the reaction was continued at room temperature for further 24 hrs. At the end of the reaction, solvent was evaporated by using a rotatory evaporator, and saturated saline was added to just dissolve the solid. Organic phase was separated, and aqueous phase was extracted with a suitable amount of diethyl ether for three times. The combined organic phase was washed well with saturated saline, then dried over anhydrous sodium sulfate. Solvent was removed by using a rotatory evaporator, and the residue was distilled under reduced pressure to give 0.084 mol of product. Yield 70%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:22])=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)#[N:26]
Reactant: CN(CCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.33 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=612 ([M+H]+, 49), 229 (100); IR (KBr): 2165 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanol/ether solvent mixture; m.p.: 137° C. (ethanol/ether).
Reaction SMILES: [N:1]1([C:6]2([Li])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:16](Cl)([Cl:19])([CH3:18])[CH3:17]>C1COCC1>[Cl:19][Si:16]([CH3:18])([CH3:17])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:7]1
Reactant: [Li]C1(N2CCCC2)C=Cc2ccccc21
Reactant: C[Si](C)(Cl)Cl
Solvent: C1CCOC1
Product: C[Si](C)(Cl)C1C=C(N2CCCC2)c2ccccc21
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of (1-(1-pyrrolidinyl)-1H-indenyl)lithium (2.0) g. 10.46 mmol) in 25 mL of THF was added within 30 minutes to a 50 mL THF solution containing SiMe2Cl2 (8.1 g, 62.76 mmol). After the addition was complete the reaction mixture was stirred overnight. The solvent was then removed under reduced pressure. The residue was extracted with hexane and the solution was filtered. The solvent was then removed under reduced pressure leaving 2.40 g of product. Yield 82 percent.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+].BrC[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CCOCC.CN(C=O)C>[CH2:22]([O:25][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:13]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1csc(Nc2cc(Oc3ccccc3O)ccn2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cccc(OCc4ccccc4)c3)ccn2)n1
Yield: 38.4 %

Procedure:
A mixture (2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenol (0.150 g, 0.501-mmol), potassium carbonate (0.208 g, 1.50 mmol), 1-(bromomethyl)benzene (0.0857 g, 0.501 mmol), and DMF (2 mL) was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate was washed with water and brine, dried and concentrated. The residue was purified via MPLC (Biotage) eluting with 7:3 hexane:ethyl acetate to afford the free base. The free base was dissolved in ether (4 mL) and 1M HCl in ether (1 mL) was added. The mixture was diluted with hexanes (5 mL) and triturated. The solids were collected by filtration, washed with hexanes, and dried to afford the desired product (0.075 g, 35.1% yield) as a white powder. 1H NMR (d6-DMSO) δ 10.5 (bs, 1H), 8.24 (d, 1H), 7.33-7.47 (m, 6H), 6.98 (d, 1H), 6.90 (s, 1H), 6.80 (d, 1H), 6.58-6.60 (m, 3H), 5.13 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](I)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:7][CH2:2][CH2:3][CH3:4])[N:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)c1c(O)cc(O)nc1C(F)(F)F
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cc(OCCCC)c(C(=O)OCC)c(C(F)(F)F)n1
Yield: 198.8 %

Procedure:
A mechanically stirred mixture of 22.6 g (0.09 mol) of product of Example 1, 99 g of butyl iodide, 24.84 g of potassium carbonate and 250 ml of acetone was held at reflux for 26 hours and filtered. The acetone filtrate was concentrated and the residue was dissolved in ether. The ether solution was washed with water, dried, and concentrated. The residue was kugelrohr distilled at 0.3 torr to give 32.5 g (99%) of product, nD25 1.4543.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C1COCC1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCC>[C:17]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: c1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
1-Bromoadamantane (215.4 mg, 1.0 mmol) and a THF solution (1.55 mL, 0.97 M, 1.50 mmol) of phenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of phenylmagnesium bromide was added dropwise at 40° C. over 3 hours. After silica gel column chromatography (pentane), the title compound was obtained as a white solid (0.173 g, yield 81%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[C:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.Cl>CCO>[CH3:19][N:16]1[CH2:17][CH2:18][C:13](=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([OH:20])=[O:4])[CH2:14][CH2:15]1
Reactant: COC(=O)c1ccccc1C=C1CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(=Cc2ccccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1M NaOH (2 mL; 2 mmol; 4.9 eq.) was added to a solution 2-(1-methyl-piperidin-4-ylidenemethyl)-benzoic acid methyl ester (100 mg; 0.41 mmol; 1 eq.) in EtOH (2 mL) and the reaction mixture was stirred at room temperature for 16 hours. The pH was adjusted to 5 with 1M HCl and the solution was concentrated in vacuo to afford the title compound as a white solid which was used without further purification. HPLC (max plot) 99.1%; Rt 1.69 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCCCC)CCC.[Cu]>[CH3:26][N:23]1[CH2:22][CH2:21][N:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:27])=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:25][CH2:24]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccccc3N)cc2)CC1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccccc3Nc3ccccc3)cc2)CC1
Temperature: 160 °C

Procedure:
A mixture of 1-(2-aminophenyl)-3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propan-1-one (1.16 g), copper powder (90 mg), KI (19.7 mg), K2CO3 (495 mg) and iodobenzene (1.3 mL) in dibutyl ether (25 mL) was heated at 160° C. (oil bath temperature) overnight. A second aliquot of KI (19.7 mg), K2CO3 (495 mg) and iodobenzene (1.30 mL) was added, and the resulting mixture again heated at 160° C. overnight. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and EtOAc (50 mL), the organic layer separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 98:2 for 5 minutes, 95:5 from minutes 10 to 15) to afford 3-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-1-(2-phenylaminophenyl)-propan-1-one (258 mg). MS=464.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]([NH2:21])=O)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1COCC1>[CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19](=[S:31])[NH2:21])[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Yield: 87.4 %

Procedure:
A solution of the compound (284 mg, 0.99 mmol) obtained in step 1 and Lawesson's reagent (360 mg, 0.89 mmol) in THF (4 mL) was stirred at 60° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 5→95% ethyl acetate/hexane) to give 1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide (236 mg, 0.778 mmol, 79%) as a white powder.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:21]([C:19]2[NH:18][C:15]3=[N:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)[CH:13]=[C:14]3[CH:20]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Reactant: C1CCNCC1
Agent: Cl
Product: O=C(c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1)N1CCCCC1
Yield: 75 %

Procedure:
The title compound was synthesized in analogy to example 1 from 5-(3-piperidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride and piperidine to give the desired product as a light brown solid (75%).
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:24]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:4]1[CH:3]=[C:2]([Cl:1])[C:22]([Cl:23])=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4,5-dichloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4,5-dichloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O[NH:64][C:65]([C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH:68]=1)=[NH:66]>CN(C=O)C>[CH:68]1[C:69]2[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:75]=[CH:76][C:67]=1[C:65]1[N:64]=[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[O:12][N:66]=1
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(NO)c1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc3ccccc3c2)no1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid (1 eq), TBTU (1.2 eq), HOBt (0.2 eq) and DIPEA (5 eq) in DMF was stirred at RT for 5 min; then added N-hydroxynaphthalene-2-carboximidamide was added and the mixture was stirred at RT for 20 min, after which time the mixture was warmed to 110° C. for 2 h. The solvent was removed under reduced pressure and the resulting crude used as such in the next step. MS (ES) C26H33N3O4 requires: 451, found: 452 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][NH:30][CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1>>[ClH:1].[ClH:14].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][N:30]([C:2]4[C:3]5[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=5[N:5]=[CH:6][N:7]=4)[CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: NC(c1ccc(Cl)cc1)c1nnc2n1CCNC2
Agent: Cl
Product: C[C@@H]1CCc2ncnc(N3CCn4c(nnc4C(N)c4ccc(Cl)cc4)C3)c21
Yield: 64 %

Procedure:
Using the procedure from Example 8, Step 5, using (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (100 mg, 0.30 mmol) to afford (4-chlorophenyl)(7-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (75 mg, 0.19 mmol, 64%): LCMS APCI+(M+H+): 396 (60%), 398 (20%), rt 2.48 min. HPLC purity at 254 nm >99%, rt=1.68 min. 1H NMR (400 MHz, d6-DMSO) □ 9.51 (s, 3H), 8.85 (d, J=9.4 Hz, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.55 (d, J=7.8 Hz, 2H), 6.08 (br d, J=9.0 Hz, 1H), 5.42 (dd, J=26 Hz, 16 Hz, 1H), 5.19 (dd, J=21 Hz, 18 Hz, 1H), 4.55 (m, 1H), 4.29 (m, 1H), 3.79 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.32 (m, 1H), 1.82 (m, 1H), 1.15 (t, J=6.8 Hz, 2H), 1.04 (d, J=6.2 Hz, 3H).
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C#CC3N(C)C=NC=3)C=2)C=1.Br[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[C:40]([NH:42][CH:43]3[CH2:45][CH2:44]3)[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=2)[CH:33]=[N:34][CH:35]=1.[CH:52]([N:55]1[CH2:60][CH2:59][N:58]([CH2:61][C:62]#[CH:63])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]>>[CH:43]1([NH:42][C:40]2[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=[C:36]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([C:63]#[C:62][CH2:61][N:58]4[CH2:57][CH2:56][N:55]([CH:52]([CH3:54])[CH3:53])[CH2:60][CH2:59]4)[CH:31]=3)[CH:41]=2)[CH2:45][CH2:44]1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Reactant: C#CCN1CCN(C(C)C)CC1
Agent: CNc1cc(-c2cncc(C#Cc3cncn3C)c2)cc(-c2ccccn2)n1
Product: CC(C)N1CCN(CC#Cc2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)CC1

Procedure:
is prepared analogously to Methyl-[5″-(3-methyl-3H-imidazol-4-ylethynyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.182) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) and by replacing 1-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole with 1-isopropyl-4-(prop-2-ynyl)piperazine (Intermediate D1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[CH:4][C:5]([Cl:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Br:12][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH:8]([O:10][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:9])=[CH:7][C:2]=1[NH2:1]
Reactant: CC(O)c1cc(N)c(Br)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cc(N)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
To a solution of 1-(5-amino-4-bromo-2-chloro-phenyl)-ethanol (0.195 g, 0.778 mmol) in DMF (3 ml) was added tert-butyl-dimethylsilyl chloride (0.152 g, 1.011 mmol) and imidazole (0.069 g, 1.011 mmol). The mixture was stirred at room temperature for six hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 2-bromo-5-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-chloro-phenylamine (0.262 g, 92%) as a clear oil.