Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])[N:17]=[C:16]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCN
Product: CCS(=O)(=O)NCCOc1nc(-c2ncccn2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 129 mg 5isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with ethanesulfonylchloride to give 130 mg 5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.54 min, [M+1]+=630.59, [M−1]−=628.69.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:27]=3)=[C:20]([C:39]([F:42])([F:41])[F:40])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:44]>C(O)C>[ClH:44].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:27]=2)=[C:20]([C:39]([F:40])([F:41])[F:42])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCc3cccc(Oc4ccccc4)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCc2cccc(Oc3ccccc3)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 7-1 (850 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (603 mg) as a white powder.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:9]([NH2:11])[CH3:10])=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC=C(CC(C2C=CC(Cl)=CC=2)C(N[CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)C)C=1.ClC1C=CC(C2C=CC(CC(C3C=CC(Cl)=CC=3)C(NCC3C=CC4C(=CC=CC=4)C=3)C)=CC=2)=CC=1.ClC1C=CC(C(CC2C=CC(C3C=CC=CC=3)=C(F)C=2)C(NCC2C=CC3C(=CC=CC=3)C=2)C)=CC=1.ClC1C=CC(C(CC2C=C(C3C=CC=CC=3)C(F)=CC=2)C(NCC2C=CC3C(=CC=CC=3)C=2)C)=CC=1.ClC1C=CC(C(CC2C=CC=C(C3C=CC4C(=CC=CC=4)C=3)C=2)C(NCC2C=CC3C(=CC=CC=3)C=2)C)=CC=1.C1(C2C=CC=CC=2)C=CC(CC(C2C=CC(Cl)=C(Cl)C=2)C(NCC2C=CC3C(=CC=CC=3)C=2)C)=CC=1.C1(C2C=CC=CC=2)C=CC(CC(C2C=CC3C(=CC=CC=3)C=2)C(NCC2C=CC3C(=CC=CC=3)C=2)C)=CC=1>>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:9]([NH:11][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)[CH3:10])=[CH:5][CH:6]=1
Reactant: CC(NCc1ccc2ccccc2c1)C(Cc1cccc(-c2ccccc2)c1)c1ccc(Cl)cc1
Reactant: CC(N)C(Cc1ccc(-c2ccccc2)cc1)c1ccc(Cl)cc1
Agent: CC(NCc1ccc2ccccc2c1)C(Cc1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(Cl)cc1
Agent: CC(NCc1ccc2ccccc2c1)C(Cc1ccc(-c2ccccc2)c(F)c1)c1ccc(Cl)cc1
Agent: CC(NCc1ccc2ccccc2c1)C(Cc1ccc(-c2ccccc2)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(NCc1ccc2ccccc2c1)C(Cc1ccc(-c2ccccc2)cc1)c1ccc(Cl)cc1

Procedure:
The following compounds were prepared in the same manner as in Reference Example 2 except that (1RS,2RS)-3-(4-biphenylyl)-2-(4-chlorophenyl)-1-methylpropylamine used in the above reaction was changed to the corresponding amine compounds: N-{(1RS,2RS)-3-(3-biphenylyl)-2-(4-chlorophenyl)-1-methylpropyl}-2-naphthylmethylamine, N-{(1RS,2RS)-3-(4'-chloro-4-biphenylyl)-2-(4-chlorophenyl)-1-methylpropyl}-2-naphthylmethylamine, N-{(1RS,2RS)-2-(4-chlorophenyl)-3-(2-fluoro-4-biphenylyl)-1-methylpropyl}-2-naphthylmethylamine, N-{(1RS,2RS)-2-(4-chlorophenyl)-3-(6-fluoro-3-biphenylyl)-1-methylpropyl}-2-naphthylmethylamine, N-[(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-{3-(2-naphthyl)phenyl}propyl]-2-naphthylmethylamine, N-{(1RS,2RS)-3-(4-biphenylyl)-2-(3,4-dichlorophenyl)-1-methylpropyl}-2-naphthylmethylamine and N-{(1RS,2RS)-3-(4-biphenylyl)-1-methyl-2-(2-naphthyl)propyl}-2-naphthylmethylamine.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]([NH:10][C:11](=[O:18])[NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27]O>S(=O)(=O)(O)O.O>[CH3:27][O:16][C:15](=[O:17])[CH2:14][CH2:13][NH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: CO
Reactant: O=C(O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
A solution of 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid (20 mg, 0.05 mmol) in methanol (5 mL) was treated with concentrated sulfuric acid (4 drops). This solution was heated to 80° C. for 8 h. At this time, the reaction was cooled to 25° C. and diluted with water (10 mL). This solution extracted with ethyl acetate (3×20 mL). The organics were washed with a saturated aqueous sodium bicarbonate solution (1×20 mL), a saturated aqueous sodium chloride solution (1×20 mL) and water (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid methyl ester (18 mg, 86%) as a white solid: 93.6-95.8° C.: EI-HRMS m/e calcd for C19H24Cl2N2O4 (M+) 414.1113, found 414.1114.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:6]23)[CH2:3][CH2:2]1.[H-].[Na+].C(OCC)(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH:1]1([CH2:4][N:5]2[C:6]3[C:7](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]([OH:10])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]2=[O:12])[CH2:2][CH2:3]1
Reactant: O=c1oc(=O)n(CC2CC2)c2ccccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2ccccc2n(CC2CC2)c1=O

Procedure:
Reagents: Comp 20 (1.38 mmols, 0.3 g); Sodium hydride (2.91 mmols, 0.07 g); Diethyl malonate (6.91 mmols, 1.1 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.S(O)(O)(=O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[NH:15].C(=O)([O-])O.[Na+]>ClC1C=CC(Cl)=CC=1Cl>[CH3:1][O:2][CH2:3][C:4]1[NH:15][C:14]([NH2:16])=[N:13][N:12]=1
Reactant: COCC(=O)O
Reactant: N=C(N)NN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: COCc1nnc(N)[nH]1
Temperature: 200 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of methoxyacetic acid (15 g), aminoguanidine sulfate (21 g) and 1,2,4-trichlorobenzene (20 mL) was stirred at 200° C. for 24 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with n-butanol. The obtained n-butanol layer was concentrated, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (15 g, 75%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][CH:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]1)[O:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[C:33]1([C:39]2[CH:46]=[CH:45][C:42](C=O)=[CH:41][CH:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[B-]C#N.[Na+].C(O)(=O)C>FC(F)(F)C(O)=O>[C:33]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:45][CH:46]=2)[CH:38]=[CH:37][C:36]([CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][N:10]4[CH2:9]3)[CH2:18][CH2:17]2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cn2c(n1)OC(CN1CCN(Cc3ccc(-c4ccccc4)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 319 (400 mg, 1.13 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride (10 ml) and neutralized with triethylamine (2 ml, 14.35 mmol). The resulting solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (515 mg, 2.83 mmol), sodium cyanotrihydroborate (214 mg, 3.41 mmol) and acetic acid (0.21 mg, 3.67 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated. To the residue, water was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogen-carbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford 2-[4-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (188 mg, yield 40%) as a white powder.
Reaction SMILES: C([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]1=[O:25])C=C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]1=[O:25]
Reactant: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(C)cc(c23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: Cc1cc2c3c(ccc(N4CCCC4)c3c1)C(=O)N(O)C2=O
Yield: 65.6 %

Procedure:
Following the procedure of Example 59, 2-allyloxy-5-methyl-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.55 g, 1.8 mmol, from Example J2), phenylsilane (0.29 g, 2.6 mmol), Pd(PPh3)4 (0.81 g, 0.070 mmol) in CH2Cl2 (40 mL) were reacted to give 0.35 g of the title compound, mp 236-237° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[C:22]([Br:24])[CH:21]=[C:20](Br)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:26][N:27]([CH3:30])C=O>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[C:22]([Br:24])[CH:21]=[C:20]([C:2]4[CH:30]=[N:27][C:26]([C:16]([OH:17])([CH3:7])[CH3:15])=[CH:3][CH:1]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(NC1CC1)c1cn(-c2cc(Br)cc(Br)c2)c2ncccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(C)(O)c1ccc(-c2cc(Br)cc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cn1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A mixture of N-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2,2-(1-hydroxy-1-methylethyl)-5-tributylstannylpyridine from Step 3 (1.4 eq), 1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq), and cuprous iodide (0.05 eq) in N,N-dimethylformamide (15 ml/mmol) was stirred at 85° C. for 5 hours. After cooling the resulting mixture was partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:6:3 mixture of ethanol, ethyl acetate and methylene chloride to afford the N-Cyclopropyl-1-{5-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:21][C:22]([CH2:25]Cl)=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:25][C:22]3[S:21][C:20]([Cl:19])=[CH:24][CH:23]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)s2)CCO1)Nc1ccc(Cl)cc1
Yield: 66 %

Procedure:
Example 37 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 2-chloro-5-(chloromethyl)thiophene (0.0068 g) to give the title compound (0.0098 g). LC-MS (System A): Rt 2.84 mins, Mass Spectrum m/z 400 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:13][CH2:12][CH2:11][Br:10]
Reactant: BrCCCBr
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Clc1ccc(OCCCBr)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 3,4-dichlorophenol (499.4 g. 3.06 moles), 1,3-dibromopropane (2424 ml, 12 moles), 24% sodium hydroxide (613 g, 3.83 moles), and 5 g of tetrabutylammonium hydrogen sulfate were stirred and heated at 50-70° C. for 2 h. The temperature was raised to 80° and heating was continued for 16 hr more. After cooling the lower phase was separated and excess dibromopropane was removed on a rotary evaporator. The residue was distilled through a short vigreux column at 1 mm vacuum. A total of 870 g (87.3%) of product was collected at 125-135° C. 1H-NMR (CDCl3) & 2.23 (m, 2H), 3.50 (t, 2H), 4.02 (t, 2H), 6.7-7.2 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:34])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=O)[C:16]=3[CH:15]=[CH:14][C:13]=2[N:33]=1.B.CSC.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:34])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][CH2:25][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[C:16]=3[CH:15]=[CH:14][C:13]=2[N:33]=1
Reactant: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CC(=O)N1CCOCC1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.7 %

Procedure:
A stirred suspension of the product of Example 7 (85 mg, 0.17 mmol) in THF (9 mL) was heated to reflux and borane-methylsulfide (0.09 mL, 0.9 mmol) added. Stirring was continued for 3.5 h at reflux and overnight at room temperature. 6M HCl was added and the solution stirred for 2 h. The solution was applied to a Varian SCX column, washed with MeOH/CH2Cl2 50:50, then the product eluted with MeOH/CH2Cl2/NH4OH 50:50:1. The product was further purified on a silica column eluting with CH2Cl2/MeOH 98:2 to give the title compound 32 mg, 39%, mp 285-290° C.; MS (ES) 486,488 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([F:24])=[C:18]([CH:21]=[CH:22][CH:23]=4)[CH:19]=[O:20])=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1.[CH3:26][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([F:24])=[C:18]([CH:19]([OH:20])[CH3:26])[CH:21]=[CH:22][CH:23]=4)=[CH:12][N:11]3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(O)c1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Temperature: 0 °C

Procedure:
170 mg of 3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-2-fluorobenzaldehyde (compound obtained according to protocol described in Example 1.2) are placed under a stream of argon in a round-bottomed flask and dissolved in 30 ml of tetrahydrofuran. The solution is cooled to 0° C. with an ice bath and 2.60 ml of a solution, standardized beforehand at 0.56M, of methylmagnesium bromide in dibutyl ether are added dropwise. The mixture is left stirring in the ice bath for one hour and then 5 ml of a saturated aqueous ammonium chloride solution are added. The organic phase is separated and dried over sodium sulphate. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture. 64 mg of compound are obtained. M.p.=193-195° C. 1H NMR spectrum (d6-DMSO, δ in ppm): 1.4 (d, 3H); 5.1 (m, 1H); 5.35 (d, 1H); 7.35 (m, 1H); from 7.45 to 7.65 (m, 5H); 7.7 (d, 1H); 8.05 (d, 2H); 8.5 (s, 1H); 8.75 (s, 1H). M+H=367.
Reaction SMILES: Br[C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[CH:7]([CH3:15])[CH2:6][CH2:5]2.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>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.O1CCOCC1>[CH3:15][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[C:3]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccccc3)c2CCC1C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)c(Oc3ccccc3)c2CCC1C
Temperature: 80 °C

Procedure:
A screw-cap vial equipped with a magnetic stir bar was charged with rac-1-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.024 g, 0.067 mmol), 4-(methylsulfonyl)phenylboronic acid (0.020 g, 0.100 mmol), 1,4-dioxane (0.67 mL), 1.0 M aqueous sodium bicarbonate (0.200 mL, 0.200 mmol), and bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 6.7 μmol). The vial was flushed with nitrogen and then capped. The reaction mixture was then heated to 80° C. for 3 h and then cooled to room temperature. The reaction mixture was diluted with 5% aqueous sodium chloride solution (0.5 mL) and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were concentrated under reduced pressure to afford a dark brown residue, which was then purified by preparative thin layer chromatography (1×1000 micron plate; eluting with 3:2 ethyl acetate-hexanes). The major band was isolated (26 mg) and further purified by preparative HPLC to afford rac-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone. 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (d, J=6.60 Hz, 3H), 1.45 (br s, 1H), 2.07-2.24 (m, 1H), 2.27 (s, 3H), 2.29-2.37 (m, 1H), 2.71 (dt, J=16.13, 6.42 Hz, 1H), 3.01 (s, 3H), 4.79 (br s, 1H), 6.59-6.69 (m, 2H), 6.82-6.95 (m, 1H), 7.15 (t, J=7.70 Hz, 2H), 7.32 (br d, J=7.33 Hz, 2H), 7.65 (d, J=8.43 Hz, 2H), 7.84 (d, J=8.43 Hz, 2H). MS (ESI, pos. ion) m/z 436 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[CH3:21][C:19]1[C:18]([NH2:22])=[N:17][CH:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)cnc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC2CCNCC2)cnc1N

Procedure:
A solution of 4-(6-amino-5-methyl-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.84 g, 9.27 mmol) in dioxane (30 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 207.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[C:29]#[N:30].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O.O.C(O)(C(F)(F)F)=O.C(#N)C>CN(C=O)C>[C:29]([C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([CH2:19][CH2:18][NH:17][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([CH:5]4[CH2:4][CH2:3][C:2](=[O:1])[NH:7][CH2:6]4)=[CH:16][CH:15]=3)[CH:21]=2)[NH:25][CH:24]=1)#[N:30]
Reactant: N#Cc1c[nH]c2ccc(CCN)cc12
Reactant: O=C1CCC(c2ccc(C(=O)O)cc2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(C4CCC(=O)NC4)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(6-Oxo-piperidin-3-yl)-benzoic acid (190 mg, 0.87 mmol, reference example 65) and 5-(2-amino-ethyl)-1H-indole-3-carbonitrile (161 mg, 0.87 mmol, reference example 2) is dissolved in anhydrous DMF (3 mL). To this solution is added diisoproplyethylamine (330 μl, 1.9 mmol), followed by HBTU (330 mg, 0.87 mmol) and allowed to stir at room temperature overnight (16 hours). The product is isolated by Reverse-Phase chromatography of the crude reaction mixture (Dynamax C-18 60 A (5×30 cm), 50 ml/min, λ@ 220 nm, 10-70% B in 15 minutes, A: 0.1% TFA/water, B: 0.1% TFA/acetonitrile). 1H NMR (300 MHz, DMSO) δ 1.94 (m, 2H), 2.26 (m, 2H), 2.92 (t, J=7.1, 2H), 3.19 (m, 1H), 3.48 (m, 2H), 3.46 (m, 2H), 7.13 (d, J=8.4, 1H), 7.15 (d, J=1.4, 2H), 7.36 (d, J=8.3, 2H), 7.43 (d, J=8.5, 1H), 7.46 (s, 1H), 7.55 (d, J=2.5, 1H), 7.73 (d, J=8.3, 2H), 8.17 (d, J=3.0, 1H), 8.47 (t, J=5.5, 1H). MS (Ion spray) m/z 387 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[F-:14].[Cs+].F.[K]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])/[CH:4]=[C:5](/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)\[F:14]
Reactant: COC(=O)C#Cc1ccc(Cl)cc1
Reactant: [F-]
Agent: F
Agent: [Cs+]
Agent: [K]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\F)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of (4-chloro-phenyl)-propynoic acid methyl ester (5.36 g) in dimethylformamide (60 ml) was added cesium fluoride (11.4 g) and potassium hydrogen fluoride (2.73 g) in water (5.4 ml) and the mixture was stirred at 80° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), the organic phase washed with water (3×50 ml) and brine (3×20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate:cyclohexan 1:9) to give 1.06 g of the desired product (20%) which was characterized by its mass and NMR spectra.