Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[N+:19]([O-])=O)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:10]=2[NH2:19])[CH2:6][CH2:7]1
Reactant: CN1CCN(Cc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2ccc(C(F)(F)F)cc2N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-methyl-4-(2-nitro-4-trifluoromethyl-benzyl)-piperazine (543 mg, 1.8 mmol) in MeOH (18 mL) was added 10% Pd/C (95 mg, 0.09 mmol). The mixture was stirred under an atmosphere of hydrogen at RT for 2 h. The resulting mixture was filtered through a pad of Celite and concentrated to yield 2-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine. MS m/z=274 [M+1]+. Calc'd for C13H18F3N3: 273.30.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH2:12][CH2:13][Cl:14])[N:8]=[N:9]2)=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].C([O-])([O-])=O.[Na+].[Na+].N>C(O)(C)C.C1(C)C=CC=CC=1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][CH2:13][CH2:12][C:7]1[N:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:21]1[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)[CH:11]=2
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: ClCCc1nnc2cc(Br)ccc2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc3cc(CCCl)nnc3c2)cc1
Temperature: 90 °C
Yield: 50 %

Procedure:
A mixture of the product from Example 169C (0.095 g, 0.312 mmol), 4-cyanophenylboronic acid (0.046 g, 0.343 mmol), Pd(PPh3)2Cl2 (0.011 g, 0.016 mmol), and 1 M Na2CO3 (0.778 mL, 0.778 mmol) in de-gassed isopropanol/toluene (5 mL, 1:1) was heated to 90° C. under a dry nitrogen atmosphere for 24 hours. After cooling, the reaction mixture was diluted with 20 mL water, extracted twice with 25 mL dichloromethane, and concentrated under reduced pressure. The crude material was purified by column chromatography (100% dichloromethane to 99:1 dichloromethane/methanol) to afford the product in 50% yield as a brown-orange solid. 1H NMR (CDCl3, 300 MHz) δ 8.76 (d, J=3 Hz, 1H), 8.02 (dd, J=3, 9 Hz, 1H), 7.96 (d, J=9 Hz, 1H), 7.87 (q, J=9 Hz, 4H), 7.80 (s, 1H), 4.14 (t, J=6 Hz, 2H), 3.69 (t, J=6 Hz, 2H). MS (DCI-NH3) [M-Cl]+ at 258, [M+H]+ at 294.
Reaction SMILES: [CH3:1][C:2]1C=NNC=1.C(=O)CC.[CH:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])OCC.[N+]([O-])([O-])=O.[NH4+]>C(O)C>[CH2:19]([O:18][CH:11]([O:15][CH2:16][CH3:17])[CH2:1][CH3:2])[CH3:20]
Reactant: Cc1cn[nH]c1
Reactant: CCOC(OCC)OCC
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCC=O
Product: CCOC(CC)OCC

Procedure:
In the first step of the present synthesis of 4-MP, propionaldehyde is reacted with triethyl orthoformate in the presence of ethanol and ammonium nitrate to produce 1,1-diethoxypropane. In the second step, the 1,1-diethoxypropane produced in the first step is reacted neat (without a solvent) with a catalyst, which comprises an acid and an amine, to produce 1-ethoxy-1-propene (ethyl-1-propenyl ether). In the third step, this material is purified by washing and drying, without distillation. In the fourth step, the 1-ethoxy-1-propene from the third step is reacted with triethyl orthoformate in the presence of boron trifluoride-diethyl etherate to produce 1,1,3,3-tetraethoxy-2-methyl propane (“TEMP”). In the fifth step, the TEMP from the third step is reacted with hydrazine or a hydrazonium salt or hydrazine hydrate at elevated temperatures to produce 4-methylpyrazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([C:27]([F:30])([F:29])[F:28])([C:23]([F:26])([F:25])[F:24])[OH:22])[CH2:9]2)=[CH:4][CH:3]=1.[C:31]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([N:41]3[CH2:40][CH2:39][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:43][CH2:42]3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:21]([C:23]([F:24])([F:26])[F:25])([C:27]([F:29])([F:28])[F:30])[OH:22])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
5-(4-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (500.0 mg, 0.99 mmol) prepared in Step 2 of Preparation 22, 1-BOC-piperazine (222.0 mg, 1.19 mmol), Pd2(dba)3 (45.0 mg, cat.), BINAP (62.0 mg, cat.) and sodium t-butoxide (143.0 mg, 1.49 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 340.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>CN(C1C=CN=CC=1)C.ClCCCl>[C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][CH:16]([O:19][C:26](=[O:36])[C:27]4[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])[CH2:17][CH2:18]3)[CH:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)OC1CCN(c2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1

Procedure:
The title compound was prepared by reacting 1-(2,6-diphenyl-pyrimidin-4-yl)-piperidin-4-ol (0.25 g, 0.75 mmol) with pthalic anhydride (0.335 g, 2.0 mmol) in presence of DMAP (0.13 g, 10 mmol) in solvent DCE (10 mL) at refluxing temperature for 2 hours, followed by column purification.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)[CH3:2].S(Cl)(Cl)=O.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].O>C(Cl)Cl.CCCCCC>[C:15]([NH:19][C:8]([C:6]1[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:10])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: CCc1ccc(C(=O)O)s1
Solvent: O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C(=O)NC(C)(C)C)s1
Temperature: 0 °C
Yield: 35 %

Procedure:
To a solution of 28 g (0.18 mol) of 5-ethyl-2-thiophenecarboxylic acid, from step 3a above, in 130 mL of methylene chloride was added a large excess (130 mL, 10 mol) of thionyl chloride, and the solution was heated at reflux for 2 hours. The solvent and excess reagent were removed by evaporation, and the residue was dissolved in 130 mL of chloroform and cooled to 0° C. To this solution was added 94 mL (0.9 mol) of t-butylamine dropwise, and the solution was stirred at reflux for 2 hours. The reaction was cooled, the solution poured into water, and the mixture extracted with ethyl acetate. The extract was washed with water and brine, dried, and concentrated. The residue was dissolved in ethyl acetate and the crude product was precipitated by addition of hexane. The crude product was collected by filtration and purified by flash chromatography over silica gel, eluting with 1:6 ethyl acetate:hexane, to afford 13.3 g (80% yield) of the title product after drying. MS 212 (M+H)+. NMR (CDCl3) δ: 7.25 (d, 1H, J=3 Hz), 6,72 (d, 1H, J=3 Hz), 5.70 (bs, 1H), 2.84 (q, 2H, J=7 Hz), 1.45 (s, 9H), 1.31 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Cl)nc1Cl
Reaction time: 48 h

Procedure:
19.1 g (0.1 mole) of 2,6-dichloronicotinic acid [Guthzeit and Laska, J. pr. Ch. 58 [2], 425 (1898)] are suspended in 250 ml of methanol and, while stirring and cooling with ice, hydrogen chloride gas is introduced until the mixture is saturated. The reaction mixture is allowed to stand for 48 hours at room temperature and subsequently heated for 3 hours to reflux temperature. It is then evaporated to dryness in a high vacuum at 40° C and the residue is dried in a high vacuum at 40° C. The brown crystalline product is recrystallised from ether-pentane to yield methyl 2,6-dichloronicotinate with a melting point of 53°-54° C.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][CH:22]1[CH2:29][CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:24]([CH2:34][C:35]([O:37]CC)=[O:36])[C:23]1=[O:40])[C:17]([O:19]C)=[O:18])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+].Cl>CO.O>[CH2:4]([O:3][C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][CH:22]1[CH2:29][CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:24]([CH2:34][C:35]([OH:37])=[O:36])[C:23]1=[O:40])[C:17]([OH:19])=[O:18])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CN1C(=O)C(N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)OC)CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1C(=O)C(N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)O)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(5-carbobenzyloxyamino-1-(S)-methoxycarbonylpentyl)amino]-1-ethoxycarbonylmethyl-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one (isomer B) (3.2 g) in methanol (20 ml) is added to a solution of sodium hydroxide (1.0 g) in water (3 ml). The reaction mixture is stirred at room temperature for 2 hours then acidified by the addition of 2N hydrochloric acid. The solution is evaporated under reduced pressure to give 3-[(5-benzyloxycarbonylamino-1-(S)-carboxypentyl)amino]-1-carboxymethyl-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one (Isomer B).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]CBr)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([O:6][C:5]4[CH:20]=[CH:21][C:2]([NH2:1])=[CH:3][CH:4]=4)=[CH:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[C:17]#[N:18])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(N)cc4)c3cc2C#N)CC1

Procedure:
After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) with sodium hydride in dimethylformamide in the same manner as Production Example 713-2, it was reacted with 4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain the title compound (225 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH3:19])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C@@H:13]4[O:17][CH3:18].COC1C=CC2[C@H]3CC[C@@]4(C)[C@H]([C@@H]3CCC=2C=1)CCC4=O>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]2[C:9]3=[CH:10][CH2:11][C@@:12]4([CH3:19])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C@@H:13]4[O:17][CH3:18]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]12
Agent: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@]2(C)[C@@H](OC)CC[C@@H]12

Procedure:
The procedure described in Example 1 hereinbefore was repeated except that 2.3 grams of 3,17β-dimethoxy-13β-methylgona-1,3,5(10)-triene was substituted for the 3-methoxy-13β-methylgona-1,3,5(10)-trien-17-one in that example.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: COc1ccc(N)cc1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OC)cc3)cc21
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol) and p-anisidine (160 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (1.2 mL, 1.8 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a brown residue that was purified by silica gel chromatography eluting with 1:1 EtOAc hexanes then EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-(4-methoxyphenylamino)-1H -[1,6]naphthyridin-2-one (87 mg, 57%): mp (2-propanol) 165-166° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+]>Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH2:26]
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cc1N
Temperature: 100 °C

Procedure:
N-(4-methyl-3-nitrophenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine 28b (7.53 mmol) and SnCl2.2H2O (33.2 mmol) are suspended in 6N HCl (40 mL). The mixture is heated at 100° C. for 3 h. The reaction vessel is chilled in an ice-water bath and 5% NaOH is added. The organic layer is extracted with EtOAc (3×50 mL), washed with brine (1×50 mL), dried over Na2SO4 and concentrated to afford 4-methyl-N1-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-yl)benzene-1,3-diamine 29b which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.54 (s, 1H), 8.84 (s, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 6.94 (dd, J=2.0 and 8.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.83 (bs, 2H), 2.07 (s, 3H). MS (m/z) (M+1)+: 361.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH2:4][CH2:3]1.FC(F)(C1C=CC(N)=CC=1OCCN1CCCC1)C(F)(F)F>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=2[C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Agent: Nc1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Product: CN1CCN(Cc2cc(N)ccc2C(F)(F)C(F)(F)F)CC1

Procedure:
3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenylamine was prepared from 1-Methyl-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine similar to that described in the preparation of 4-Pentafluoroethyl-3-(2-pyrrolidin-1-yl-ethoxy)-phenylamine.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]([PH:15](=[O:17])[OH:16])[NH:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[Si](C)(C)N[Si](C)(C)C.[CH2:28]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[CH2:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][P:15]([CH:3]([NH:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]([CH3:18])[CH3:1])([OH:16])=[O:17])[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=C(CCCCNC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CC(C)C(NC(=O)CCc1ccccc1)[PH](=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)CP(=O)(O)C(NC(=O)CCc1ccccc1)C(C)C
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
The 2-methyl-1-(3-phenylpropanoyl)aminopropylphosphinic acid (255 mg) obtained in (a) of Example 2 was added with hexamethyldisilazane (0.3 ml), and the mixture was stirred at 110° C. for 30 minutes. The mixture was then added with the ethyl 2-(4-benzyloxycarbonylaminobutyl)acrylate (356 mg) obtained in the above step (e), and further stirred at the same temperature for 18 hours. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and then the residue was purified by Sephadex LH-20 (300 cc, methylene chloride:methanol=1:1) to obtain crude ethyl 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate (222 mg, 41%). This compound was used in the following reaction without further purification. (g) The crude ethyl 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate (222 mg) obtained in the above step (f) was dissolved in a mixed solvent of ethanol:water (10:7) (3.4 ml). The mixture was added with 1 N aqueous sodium hydroxide (0.6 ml) and stirred at room temperature for 3 hours, at 50° C. for 2 hours, and then at room temperature for 16 hours. The reaction mixture was acidified with hydrochloric acid and the organic substances were extracted with ethyl acetate, and then the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was concentrated to obtain crude 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (181 mg, 86%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [OH-].[Na+].[C:3]1(CC(=O)C(O)=O)C=CC=CC=1.CI.Cl.[O:18]=[C:19]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]>C(O)(C)(C)C>[O:18]=[C:19]([C:23]([CH3:3])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)(C)O
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57 %

Procedure:
A 3N aqueous solution of sodium hydroxide (3.0 ml, 9.0 mmoles) and 6 ml of t-butyl alcohol were added to 0.492 g (3.0 mmoles) of phenylpyruvic acid to form a solution. Then, 0.6 ml of methyl iodide was added, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was acidified with 20 ml of 1N hydrochloric acid, and extracted with ether. The organic layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated under reduced pressure to give a pale while oil. The NMR spectral analysis of the product led to the determination that 2-oxo-3-phenylbutanoic acid was formed in a yield of 57 %, and 2-oxo-3-methyl-3phenylbutanoic acid, in a yield of 30 %.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccc(F)c(F)c2)nc1

Procedure:
Using the procedure outlined in Example 100, the title compound was prepared from 6-chloro-N-quinolin-7-yl-nicotinamide (D70) (40 mg, 0.14 mmol) and 3,4-difluorophenylboronic acid (27 mg, 0.17 mmol) as a cream solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.24 (dd, 1H), 8.86 (dd, 1H), 8.39 (dd, 1H), 8.28 (dd, 1H), 8.14 (br.d, 1H), 8.13 (d, 1H), 7.97 (ddd, 1H), 7.85 (m, 3H), 7.39 (dd, 1H), 7.28 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+].Cl.BrC1C=CN=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH2:22][CH2:21]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1ccncc1
Reactant: NC1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1ccc([C@H]2CCCC[C@H]2N2CCC(Nc3ccncc3)CC2)cc1
Temperature: 70 °C
Yield: 47 %

Procedure:
The title compound, MS (ISP): m/e=440.4 (M+H+), was prepared as for example 209, steps (A) to (C). Step (B) was performed using 4-bromo-pyridine as follows: A suspension of (+/−)-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-amine (0.303 g, 1.17 mmol) in toluene (10 ml) was degassed with a flow of argon for 10 minutes. Palladium(II) acetate (8.0 mg, 0.036 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP, 23.0 mg, 0.037 mmol), sodium tert-butoxide (0.280 g, 2.91 mmol) and 4-bromopyridine hydrochloride (0.194 g, 1.00 mmol) were added under argon. The flask was sealed and warmed to 70° C. for 3 hours. The mixture was diluted with ethyl acetate (10 ml) and diethyl ether (10 ml) and washed three times with saturated sodium chloride solution. The organic phase was dried with sodium sulphate and evaporated, yielding an orange oil. Purification was achieved by flash chromatography (dichloromethane/methanol/25% NH3 65:10:1). (+/−)-[cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-yl]-pyridin-4-yl-amine (0.187 g, 47%) was obtained as a light yellow foam, MS (ISP): m/e=336.3 (M+H+). This was reacted with benzoyl chloride in step (C).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#N.[OH-].[Na+]>>[NH:12]([C:10]1[NH:8][C:2]2[C:1]([CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N:7]=1)[C:13]([NH2:15])=[NH:14]
Reactant: Cc1cccc(N)c1N
Reactant: N#CNC(=N)N
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc2nc(NC(=N)N)[nH]c12
Yield: 132.4 %

Procedure:
A mixture of 2,3-toluenediamine (12.45g, 0.102 mol)(5N HCl 40. 8ml, 0.204 mol) and cyanoguanidine (8.60g, 0.102 mol) was heated on a steam bath for 1 hour. The hot solution was then basified with 40% sodium hydroxide and allowed to cool. The resulting gummy material which separated was extracted into ether. The combined ether extracts were dried (Na2SO4) and treated with ethereal hydrogen chloride to give a pink precipitate (25.55g) m.p. 213°-222°C. This crude product was recrystallised from ethanol/ether. A first crop (14.90g), m.p. 236°-238°C. which contained some unreacted 2,2-toluenediamine was obtained but a second crop (5.00g) of colourless microcrystals m.p. 249°-250°C crystallised as pure 2-guanidino-4-methylbenzimidazole dihydrochloride monohydrate.