Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:16][CH:15]3[N:17]([C:18]4[N:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1B(O)O.ClCCl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.[OH-].[Na+].C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:11][CH:12]3[N:17]([C:18]4[N:19]=[CH:20][CH:21]=[CH:22][N:23]=4)[CH:15]([CH2:14][CH2:13]3)[CH2:16]2)=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=C(c1ccc(Br)cc1)C1CC2CCC(C1)N2c1ncccn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(-c2ccc(F)cc2F)cc1)C1CC2CCC(C1)N2c1ncccn1
Yield: 18.7 %

Procedure:
A solution of (4-bromo-phenyl)-(8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-methanone (250 mg, 0.92 mmol), 2,4-di-fluoro-phenylboronic acid (290 mg, 1.84 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (67 mg, 0.092 mmol), K3PO4(390 mg, 1.84 mmol), 2-dimethoxy-ethane (5 ml) and water (1.6 ml) was stirred at 80° C. for one hour. The reaction mixture was diluted with ethyl acetate and 1N NaOH solution. The organic layer was dried by MgSO4 and concentrated. ISCO was used for purification, and the product was obtained as a white solid (2′,4′-difluoro-biphenyl-4-yl)-(8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-methanone (69.6 mg, 19%). MS (M+1)=406. 1H NMR (CDCl3) 8.34 (d, J=12 Hz 2H), 8.00 (d, J=21 Hz 2H), 7.62 (dd, J=19 Hz, 4 Hz, 2H), 7.45 (m, 1H), 6.99 (m, 2H), 6.52 (t, J=12 Hz, 1H), 4.90 (m, 2H), 4.00 (m, 1H), 2.25 (m, 2H), 2.12 (m, 2H), 2.02 (m, 2H), 1.78 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=1)=[CH:8]2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:20])=[CH:15][N:16]=1)=[CH:8]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: CN(c1cccc2cc(-c3ncc(CC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CC(=O)N4CCOCC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)acetic acid (0.38 g), morpholine (0.16 g), 1H-1,2,3-benzotriazol-1-ol (0.18 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide-hydrochloride (0.26 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. A solution of the obtained crystals in tetrahydrofuran was treated with activated carbon and concentrated to give the title compound (0.37 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate. melting point 199-200° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([C:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=O)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[N:25]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:26]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ccc(-c2nc3cc(C(=O)O)ccc3n2C2CCCCC2)cc1N
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1

Procedure:
A solution of 100 mg (0.29 mmol) of Compound 406b and 74 mg (0.35 mmol) of benzil was stirred at room temperature overnight. The solvent was evaporated and the residue was purified on preparative HPLC yielding 10 mg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3Cl)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:27][C:28]1[CH:29]=[C:30]([NH2:41])[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.ClC(Cl)C>C(O)(C)(C)C>[CH3:27][C:28]1[CH:29]=[C:30]([NH:41][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:15]#[C:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:17]=3)[N:22]=[CH:21][N:20]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc3ncnc(Cl)c3c2)CC1
Reactant: Cc1cc(N)ccc1Oc1cccnc1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2ncnc3ccc(C#CC4CCNCC4)cc23)ccc1Oc1cccnc1
Yield: 105 %

Procedure:
4-(4-Chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.21 mmol) and 3-Methyl-4-(pyridin-3-yloxy)-phenylamine (43 mg, 0.21 mmol) were mixed together in tert-butanol (1 mL) and dichloroethane (1 mL) and heated in a sealed vial at 90° C. for 20 minutes. The reaction was cooled down and HCl (gas) was bubbled through for 5 minutes. EtOAC was then added whereupon yellow precipitation occurred. The precipitate was collected and dried to afford the desired product [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine as a yellow solid (96 mg, 95%). 1H NMR (CDCl3) δ 2.01 ((m, 2H), 2.22 (m, 2H), 2.35(s, 3H), 3.20 (m, 2H), 3.45(m, 2H), 7.28 (d, 1H, J=8.7 Hz), 7.75(dd, 3H, J1=8.7, J2=8.7 Hz), 8.06 (dd, J=8.7), 8.10 (dd, J1=J2=8.7 Hz), 8.17 (m, 1 H), 8.60 (d, 1H, J=5.4 Hz), 8.80 (s, 1H), 8.89 (s, 1H). MS: M+1, 436.6.
Reaction SMILES: ClC(Cl)(Cl)C([NH:5][C:6]1[C:15]2[N:16]=[CH:17][N:18]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)=O.C[O-].[Na+]>>[S:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][N:18]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=[CH:17]1
Reactant: O=C(Nc1nc2ccccc2c2c1ncn2CCOCCCc1cccs1)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Product: Nc1nc2ccccc2c2c1ncn2CCOCCCc1cccs1
Reaction time: 30 h

Procedure:
A dried round bottom flask was charged with a stir bar, 2,2,2-trichloro-N-{1-[2-(3-thien-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-yl}acetamide and sodium methoxide (25% in methanol, 11 mL, 49.8 mmol) at ambient temperature. The reaction was judged complete after 30 hours. The volatiles were removed under reduced pressure. The resulting oil was purified with chromatography over silica gel (95/5 dichloromethane/methanol), semi-preparative HPLC using method A, and recrystallization from ethyl acetate/hexane to provide 43 mg of 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid. m.p. 130.1-131.6° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][CH2:25][NH2:26])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:26][CH2:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCCO[N+](=O)[O-])c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) and sodium methoxide (0.22 g, 4.1 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (60:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.27 g, 1.08 mmol, yield: 41%) as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[NH2:29]>>[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[NH:29][C:15]([C:7]1[C:8]2[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=1)=[O:17]
Reactant: Cc1onc(C(F)(F)F)c1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C(F)(F)F)noc3C)c2o1
Yield: 10.2 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.1 g) and 5-methyl-3-trifluoromethylisoxazol-4-ylamine (78 mg). Purification by column chromatography eluting with 20-30% ethyl acetate in hexane afforded the title compound as a white solid (16 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH:8]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:25][C:2]([F:24])([F:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:34])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(Cc1cc(OCCCC(F)(F)F)ccn1)c1nc2ccccc2[nH]1

Procedure:
The thus-obtained 2-[4-(4,4,4-trifluorobutoxy)pyridin-2-yl-methylthio]-1H-benzimidazole (1.27 g) was dissolved in methylene chloride (20 mL). A solution of 80% m-chloroperbenzoic acid (746 mg) in methylene chloride (10 mL) was added dropwise at −30° C., and the mixture was stirred for an hour at the same temperature. A saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture. The temperature of the mixture was returned to room temperature, and the mixture was stirred for 10 minutes, followed by extraction with methylene chloride. The organic layer was washed sequentially with water and brine, and brought to dryness over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel: NH-DM1020 (product of Fuji Silicia), chloroform:methanol=10:1), whereby 2-[4-(4,4,4-trifluorobutoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole was obtained (1.2 g).
Reaction SMILES: [N:1]1([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=2)[CH3:6])[CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[N:1]1([CH:5]([C:7]2[N:8]=[C:9]([NH:14][C:15]3[S:16][C:17]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][C:19]=3[C:20]([NH2:22])=[O:21])[CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: CC(c1cccc(Br)n1)N1CCC1
Product: CC(c1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)N1CCC1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(1-azetidin-1-ylethyl)-6-bromopyridine (200 mg, 0.83 mmol) and 2-amino-5-(4-fluorophenyl)thiophene-3-carboxamide (216 mg, 0.91 mmol) as the starting materials.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCO>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:16]4[CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]=[C:17]4[CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Temperature: 25 °C

Procedure:
A mixture of N-(1-adamantylmethyl)-6-aminopyridine-2-carboxamide (19.17 g, 65.2 mmol) and ethyl bromopyruvate (9.1 mL, 65.2 mmol) in EtOH (160 mL) is heated under reflux for 20 h. After cooling to RT, the solvent is removed in vacuo. The residue is partitioned between EtOAc and saturated aqueous sodium carbonate. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The brown residue is purified by re-crystallization from EtOAc and hexanes to give the title compound. 1H-NMR (δ, ppm, CDCl3 as internal standard): 9.03 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.26 (dd, J=6.9 and 9.0 Hz, 1H), 7.17 (d, J=6.9 Hz, 1H), 6.26 (m, 1H), 4.45 (q, J=6.9 Hz, 2H), 3.22 (d, J=6.6 Hz, 2H), 2.04 (m, 3H), 1.78-1.58 (m, 12H), 1.43 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][CH:37]([CH3:42])[CH2:38][CH2:39][CH2:40]O.N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:40][CH2:39][CH2:38][CH:37]([CH3:42])[CH3:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CC(C)CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, starting with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-1-pentanol in place of isobutanol (yield: 0.128 g, 85%). mp 123-125° C. 1H NMR (300 MHz, DMSO d6) δ 0.74 (d, J=6 Hz, 6H), 1.03 (m, 2H), 1.39 (m, 1H), 1.54 (m, 2H), 3.28 (s, 3H), 4.39 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.91 (m, 2H), 8.07 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 445 (M+H)+. Anal. calc. for C23H25FN2O4S: C, 62.14; H, 5.67; N, 6.30. Found: C, 62.28; H, 5.59; N, 6.25.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1>>[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21][CH2:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc2c(c1)NCCO2
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCOc2ccccc21

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 270 mg of 3,4-dihydro-2H-1,4-benzoxazine in place of the 2,4-difluoroaniline. After purification by silica column chromatography, elution being carried out with CH2Cl2/MeOH 95/05, 150 mg of 2-[2-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of 1.55 g (10 mmol) of 2-fluoro-5-nitrotoluene in 35 mL of N,N-dimethylformamide were added 1.01 g (10 mmol) of 4-hydroxypiperidine and 1.8 g (13 mmol) of potassium carbonate, and the mixture was stirred for 2 hours at 120° C. The reaction mixture was poured into ice and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 1.5 g (63%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=3[C:25]([F:28])([F:27])[F:26])[C:17]([O:19]CC)=[O:18])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3][CH:2]=1.[OH-].[Na+]>CCO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=3[C:25]([F:28])([F:26])[F:27])[C:17]([OH:19])=[O:18])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(Nc2ncccc2-c2ccncn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(F)(F)F)c(Nc2ncccc2-c2ccncn2)c1

Procedure:
Ethyl 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)benzoate (2.50 g, 6 mmol) was suspended in EtOH (30 ml) and treated with 5N Sodium hydroxide (4 ml). The mixture was stirred at reflux overnight. The reaction was cooled down and the volatiles removed in vacuo. The residue was washed with diluted acetic acid (10:1 water:acetic acid) and then washed with water, to give 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)benzoic acid as a yellow solid, after drying in a vacuum oven at 60° C. overnight. MS m/z=361 [M+1]+. Calc'd for C17H11F3N4O2: 360.08.
Reaction SMILES: C(N(C(C)C)C(C)C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[O:41][N:40]=[C:39]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:50])=[O:49])[C:45](O)=[O:46])[CH:38]=1.[O:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]1[O:59][NH2:60]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[O:41][N:40]=[C:39]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:50])=[O:49])[C:45]([NH:60][O:59][CH:54]2[CH2:55][CH2:56][CH2:57][CH2:58][O:53]2)=[O:46])[CH:38]=1
Reactant: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)no2)c1F
Reactant: NOC1CCCCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)no2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.8 %

Procedure:
N,N-Dimethy-4-aminopyridine (0.04 g, 0.3 mmol, 0.2 equiv), N-ethyl-N-isopropylpropan-2-amine (0.97 mL, 5.8 mmol, 4.5 equiv), T3P® (50% w/w solution in ethyl acetate, 3.0 mL, 4.96 mmol, 4.0 equiv), and (2R)-4-[5-(2-fluoro-3-methoxyphenyl)isoxazol-3-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.46 g, 1.24 mmol, 1.0 equiv) were allowed to stir at room temperature for 30 min. A solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.16 g, 1.3 mmol, 1.2 equiv) in ethyl acetate (15 mL) was added, and the reaction was allowed to stir overnight (18 h) at room temperature. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25 g silica gel column, 0-100% gradient ethyl acetate in hexanes) to provide (2R)-4-[5-(2-fluoro-3-methoxyphenyl)isoxazol-3-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.60 g, 10%). MS (LCMS) m/z 469.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]C)=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].O.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6]
Reactant: COC(=O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a stirred solution of methyl 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate (4.12 g, 10 mmol) in tetrahydrofuran (45 mL) and methanol (45 mL) was added lithium hydroxide hydrate (839 mg, 20 mmol) in water (18 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified using an SCX-2 cartridge eluting sequentially with methanol and 7 N methanolic ammonia. The product was triturated with THF (×5) and diethyl ether to give 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (3.51 g, 88%) as a white solid. To a solution of 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (76 mg, 0.19 mmol) in DMF (2 mL) was then added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride (Int 6, 93 mg, 0.19 mmol), followed by DMAP (11 mg, 0.1 mmol) and EDC (72 mg, 0.37 mmol). The mixture was allowed to stir at room temperature for 5 hours, and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (66 mg, 42%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:3]1.CO.[OH-].[Na+].Cl>O>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)=[N:3]1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O

Procedure:
Still following the procedure of Example 1, 6.8 g. of methyl 1-methyl-3-(4-trifluoromethylphenyl)pyrazole-5-carboxylate dissolved in 100 ml. of methanol was heated for about one hour with a solution of 1 g. of sodium hydroxide in 75 ml. of water. The reaction mixture was cooled and then acidified with 1N aqueous hydrochloric acid. The free acid, being insoluble in the acidic solution, separated and was collected by filtration. Recrystallization from benzene yielded 1-methyl-3-(4-trifluoromethylphenyl)pyrazole-5-carboxylic acid melting at 230°-2° C.