Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][C:9]3=[N:12][CH:13]=[CH:14][N:8]3[CH2:7][C:6]=2[CH:15]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][C:9]3=[N:12][CH:13]=[CH:14][N:8]3[CH2:7][C:6]=2[CH:15]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)Cn1ccnc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1 mmol of 7-chloro-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7]O)=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:17][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(-c2ccccn2)cc1CO
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccn2)cc1CCl
Temperature: 70 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethanol (3.00 g), thionyl chloride (2.5 ml) and toluene (50 ml) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 4-chloromethyl-3-methyl-1-(2-pyridyl)-1H-pyrazole (3.10 g, yield 94%) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:4][CH:3]=1.[CH2:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][C@@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:19]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:15][C:10]1[N:11]=[C:12]([N:25]2[CH2:24][CH2:23][C:22]3([CH2:18][N:19]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21]3)[CH2:27][CH2:26]2)[CH:13]=[C:8]([CH2:7][O:6][C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Nc1nc(Cl)cc(COc2ccc(Br)cc2)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(Br)cc4)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-((4-Bromophenoxy)methyl)-6-chloropyrimidin-2-amine (454 mg, 1.4 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 1.44 mmol) and NaHCO3 (605 mg, 7 mmol) in dioxane (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.[O-][Cl:12].[Na+]>CO>[Cl:12][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:6][C:2]=1[Cl:1]
Reactant: [O-]Cl
Reactant: FC(F)(F)c1cc(Cl)[nH]n1
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1n[nH]c(Cl)c1Cl

Procedure:
A solution of 5-chloro-3-trifluoromethylpyrazole (190.0 g, 1.11 mol) in 400 ml of methanol is treated with liquid bleach (5.25% NaOCl) for 3 hr. The reaction mixture is then extracted with ether, the combined ether extracts are acidified with HCl (300 ml), washed with brine, dried and concentrated to give 4,5-dichloro-3-trifluoromethylpyrazole, a light yellow solid, m.p. 58°-60° .
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:37])[CH2:28][N:27](CC3C=CC=CC=3)[CH2:26]2)=[O:24])=[CH:18][CH:17]=1.C(O)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[O:37])[CH2:26][NH:27][CH2:28]2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CN(Cc5ccccc5)C4)cc3)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CNC4)cc3)c2cc1OC
Reaction time: 16 h
Yield: 31.8 %

Procedure:
To a solution of ‘N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 0.5 mmol) in MeOH (50 mL) was charged with Pd/C (50% wet, 10% mmol, 265 mg) and acetic acid (2 mL). The reaction mixture was subjected to hydrogenolysis condition under H2 (50 psi) on a Parr Hydrogenator for 16 hr. The reaction mixture was filtered through celite and washed with MeOH. After removal of solvent in vacuo, the crude product was purified using preparative HPLC (solvent system: MeCN/H2O/NH4OAc), affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)azetidine-3,3-dicarboxamide (82 mg, 32% yield) as a white solid. 1HNMR (DMSO-d6): 8.46 (d, 1H), 7.84 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.24 (d, 2H), 7.20 (t, 2H), 6.44 (d, 1H), 4.03 (s, 4H), 3.95 (s, 6H), 1.90 (s, 3H, acetate salt). LCMS (POS): 517.3 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]1.C(N(CC)CC)C.O>C1COCC1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:8][CH:7]2[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(N)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Methanesulfonyl chloride (34 mg) was added to a solution of tert-butyl (6SR,7SR)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (90 mg) and triethylamine (33 mg) in THF (5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (90 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)CCCC)[CH:19]=[CH2:20].C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.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.O>[CH2:20]([C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1)[CH:19]=[CH2:18]
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCc1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 8 h
Yield: 30.5 %

Procedure:
In toluene (4 mL) was dissolved 200 mg (0.797 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 305 mg (0.921 mmol) of allyl(tributyl)tin, and then, 96.8 mg (0.0838 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, and then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 62.1 mg (0.243 mmol, Yield: 30.5%) of 6-allyl-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16](C#N)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH4+].[OH-]>CO.C1COCC1.[Ni]>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 111.1 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile (500 mg, 1.85 mmol) in MeOH-THF (12 mL, 5:3) was added NH4OH (1.5 mL) and Raney Ni (100 mg). The mixture was stirred for 12 h at rt under a H2 atmosphere. After filtration, the mixture was concentrated to give 5-aminomethyl-[2-(4-cyclopropylpiperazin-1-yl)benzooxazole (500 mg, 99%), which was used in the next step without further purification.
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[Na+].[I-].Cl[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:7][O:6][C:4](=[O:5])[CH2:3][S:2][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCCCl
Reactant: COC(=O)CS
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCSCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
Sodium (3.5 g, 0.15 mol) was added to methanol (150 mL) carefully. After cooling to room temperature, methyl 2-mercaptoacetate (15.6 g, 0.13 mol) was added. The mixture was stirred for 30 mins at room temperature and a little of NaI and methyl 4-chlorobutanoate 20.0 g, 0.15 mol) were added. The reaction mixture was refluxed over night. After cooling to room temperature, the solvent was removed under reduced pressure, then the residue was dissolved in CH2Cl2 (100 mL). The solution was washed with H2O (30 mL), brine (30 mL), and dried with Na2SO4. After removing the solvent, 28.3 g of the crude product was obtained (Yield: 94%).
Reaction SMILES: [C:1]([O:6]CCN1CCNC1=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]([O:20]C)(=[O:19])C(C)=C>>[C:1]([OH:6])(=[O:5])[C:2]([CH2:4][C:15]([OH:20])=[O:19])=[CH2:3]
Reactant: C=C(C)C(=O)OCCN1CCNC1=O
Reactant: C=C(C)C(=O)OC
Product: C=C(CC(=O)O)C(=O)O

Procedure:
28.50 g of a 25% strength by weight solution of N-(methacryloxyethyl) imidazolidin-2-one in methyl methacrylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([Cl:12])[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:5]2=[C:9]([Cl:12])[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: Clc1nc(Cl)c2c(Cl)ccn2n1
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1nc(NCc2ccccn2)c2c(Cl)ccn2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a stirred solution of 2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine (0.530 g, 2.38 mmol) in CH2Cl2 (20 mL) was added DIPEA (0.832 mL, 4.76 mmol) and pyridin-2-ylmethanamine (0.283 g, 2.62 mmol) and the contents were stirred for 10 min at room temperature. The reaction mixture was washed with water and the organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a brown solid. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 20% EtOAc/hexanes) to give 2,5-dichloro-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.400 g, 57.0%) as an off-white solid. LCMS Condition B-12: retention time 2.20, [M+1]=294.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.87 (d, J=5.7 Hz, 2H), 6.81 (d, J=2.8 Hz, 1H), 7.32 (t, J=1.6 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.81 (d, J=2.8 Hz, 1H), 7.83 (t, J=1.6 Hz, 1H), 8.48 (t, J=5.2 Hz, 1H), 8.57 (d, J=1.2 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:48])([CH2:46][CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=3)=[CH:35][CH:34]=2)[O:31][CH3:32])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:48])([CH2:46][CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=3)=[CH:35][CH:34]=2)[O:31][CH3:32])[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Hydrochloric acid (2N, 4 mL) was added to a solution of 2-(4-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-methoxyethyl}phenyl)-5-fluoropyridine in methanol (4 mL) at ambient temperature. The solution was stirred at 70° C. for 2 hr. Concentration of the solution afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.66-8.60 (m, 1H), 8.05-7.83 (m, 5H), 7.45-7.37 (m, 2H), 7.16 (s, 1H), 4.72-4.68 (m, 1H), 3.28 (s, 3H), 2.51 (s, 2H), 1.28-1.20 (m, 2H), 0.86 (t, J=7.0 Hz, 3H), 0.83 (s, 6H).
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([OH:12])=O)[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C[N+](C)=CCl.[Cl-].ClCCl.[CH3:28][NH:29][CH2:30][C:31]1[N:38]2[C:34]([S:35][CH:36]=[CH:37]2)=[CH:33][N:32]=1>>[C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([N:29]([CH2:30][C:31]2[N:38]3[C:34]([S:35][CH:36]=[CH:37]3)=[CH:33][N:32]=2)[CH3:28])=[O:12])[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Reactant: CNCc1ncc2sccn12
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)N(C)Cc1ncc2sccn12
Yield: 47.4 %

Procedure:
The procedure of Synthesis Example 1 is repeated, except that 260 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonylpyrrolidin-5-carboxylic acid, 0.95 ml of a 1.1 M Vilsmeier reagent/dichloromethane solution, and 159 mg of 5-(N-methylaminomethyl)imidazo[5,1-b]thiazole. Thus, 190.6 mg of the title compound is prepared as a slightly yellow amorphous material.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23](I)[CH:22]=1.[Cl-].[NH4+]>O1CCOCC1.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>[CH3:18][O:19][C:20]([C:21]1[CH:22]=[C:23]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)=[O:31]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Yield: 73.6 %

Procedure:
Phenylboronic acid (2.14 g, 17.59 mmol), potassium phosphate (4.50 g, 21.20 mmol), tetrakis(triphenylphosphine)palladium(0) (0.283 g, 0.24 mmol) and 3-iodo-5-nitro-benzoic acid methyl ester (3.00 g, 9.77 mmol) in dioxane (30 mL) were heated at 80° C. for 3 h. Saturated ammonium chloride was added and the product was extracted, washed with water, brine, dried over magnesium sulfate, and concentrated to dryness. Purification by chromatography gave 1.85 g of 5-nitro-biphenyl-3-carboxylic acid methyl ester, as a white solid.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:75])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=4)=[CH:55][C:54]=3[CH3:73])=[CH:49][CH:50]=2)[C:45]1=[O:74])[C:40]([O:42]C)=[O:41]>>[CH3:75][CH:38]([CH3:37])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:62]=[CH:63][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:65][CH:66]=4)=[CH:55][C:54]=3[CH3:73])=[CH:49][CH:50]=2)[C:45]1=[O:74])[C:40]([OH:42])=[O:41]
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(C)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(C)c2)cc1
Yield: 89 %

Procedure:
The compound of example 474 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 473.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:34][C:35]1[CH:39]=[C:38]([Sn](CCCC)(CCCC)CCCC)[O:37][N:36]=1>COCCOC.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>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=2)=[O:21])=[CH:3][C:2]=1[C:38]1[O:37][N:36]=[C:35]([CH3:34])[CH:39]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)on1

Procedure:
The title compound was synthesized in the same way as Example 29 but starting from 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (50 mg, 0.085 mmol), tetrakis(triphenylphosphine)palladium (5 mg, 0.0043 mmol) and 3-methyl-5-(tributylstannyl)isoxazole [synthesized as described in Tetrahedron, 47, 28, 5111, 1991] (63 mg, 0.169 mmol) in DME (0.85 ml). Yield: 15 mg, 0.033 mmol (39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-fluoropyridine (300 mg, 2.60 mmol) in DCM (4.0 mL), DIPEA (1.36 mL, 7.79 mmol) was added, followed by chloracetylchloride (0.23 mL, 2.86 mmol). The resulting dark brown reaction mixture was stirred at rt for 2 h, then quenched with water and diluted with DCM. The org. layer was separated and the aq. layer extracted with DCM (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 2-chloro-N-(5-fluoropyridin-2-yl)acetamide as a brown oil which was used in the next step without further purification. LC-MS conditions A: tR=0.60 min, [M+H]+=189.31.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2O[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34]>C(O)(=O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[NH:34][C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(Cc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of 2-(4-fluorobenzyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (65 mg) and ammonium acetate (256 mg) in acetic acid (1 mL) was stirred at 150° C. for four hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1). The resulting solid was suspended in diethyl ether and collected by filtration to obtain 40 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:33]=[C:32]([NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:31]3[C:26](=[CH:27][C:28]([Cl:43])=[CH:29][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1>CN(C=O)C.[Pd]>[Cl:43][C:28]1[CH:27]=[C:26]2[C:31]([C:32]([NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[N:33][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:11]4[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=4)=[CH:19][CH:20]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: CCN(CC)CCCNc1nc(-c2ccc(Br)cc2)nc2cc(Cl)ccc12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2ccc(-c3ccc(Cl)cc3)cc2)nc2cc(Cl)ccc12

Procedure:
1,2 Equivalents of K2CO3, 1,2 equivalents of 4-chlorophenylboronic acid and 10 mol % of Pd((PPh3)4 are added to a solution of N′-[2-(4-bromo-phenyl)-7-chloro-quinazolin4-yl]-N,N-diethyl-propane-1,3-diamine (16,5 mmol) in 80 ml of DMF and it is heated at 80° until conversion is complete. After filtering off the catalyst and customary working up for solution reactions, N′-[7-chloro-2-(4′-chloro-biphenyl-4-yl)-quinazolin-4-yl]-N,N-diethyl-propane-1,3-diamine is obtained.
Reaction SMILES: [BrH:1].C([NH:9][CH:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=1)[CH2:11][OH:12])C1C=CC=CC=1.C>CO>[BrH:1].[NH2:9][CH:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=1)[CH2:11][OH:12]
Reactant: Cc1ccc(CC(CO)NCc2ccccc2)cc1O
Agent: Br
Solvent: CO
Product: Cc1ccc(CC(N)CO)cc1O
Yield: 81.3 %

Procedure:
21.5 gm (61 millimols) of 2-benzylamino-3-(3'-hydroxy-4'-methyl-phenyl)-1-propanol hydrobromide (see Example 2) were dissolved in 250 ml of methanol, 6 gm of 5% palladized charcoal were added to the solution, and the mixture was hydrogenated at 60° C and 5 atmospheres pressure. After the debenzylation had gone to completion, the reaction mixture was filtered, the methanol was distilled in vacuo out of the filtrate, the residue was dissolved in hot acetonitrile, and the solution was allowed to cool. The substance which crystallized out was collected by suction filtration and dried, yielding 13 gm (81.5% of theory) of 2-amino-3-(3'-hydroxy-4'-methyl-phenyl)-1-propanol hydrobromide having a melting point of 115°-117° C.