Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.Cl.[CH3:19][O:20][NH2:21].C[O-].[Na+]>CO>[CH3:19][O:20][N:21]=[CH:1][C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1=Cc2cccc(C=O)c2OCC1
Reactant: CON
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=Cc1cccc2c1OCCC(C(=O)OC)=C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Methyl 2,3-dihydro-9-formyl-1-benzoxepin-4-carboxylate (0.5 g) was added to a mixture of O-methylhydroxylamine hydrochloride (0.25 g) and 28% sodium methoxide in methanol (0.5 ml) in methanol (5 ml) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give methyl 2,3-dihydro-9-methoxyiminomethyl-1-benzoxepin-4-carboxylate (0.55 g).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccccc1
Product: Nc1nnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 43.3 %

Procedure:
5,6-Diphenyl-1,2,4-triazin-3-amine (86.0 mg, 42%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.8 mmol) and phenyl boronic acid (0.11 g, 0.92 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>O>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH2:31][CH2:30][N:29]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
p-Toluenesulfonyl chloride (4.39 g, 23 mmol) was added to a pyridine solution (30 ml) of 4-(4-methoxyphenyl)piperidine (4.0 g, 21 mmol) and the mixture was stirred at room temperature overnight. Water was added to the solution mixture, which was then extracted with ethyl acetate. The organic phase was washed with hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated to dryness under reduced pressure to obtain 4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)piperidine (4.8 g) as white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([N:16]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)[CH2:17][CH3:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ClCCl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH2:14][N:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=1)[CH2:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)C(=O)c2sccc2OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(CC)Cc2sccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
Borane-tetrahydrofuran complex (2.7 mL of a 1.0M solution in THF) was added over 5 minutes to a solution of ethyl 4-[N-(3-benzyloxy-2-thienoyl)-N-(ethyl)amino]benzoate (1.0 g) in THF (10 mL). The reaction mixture was stirred at ambient temperature for 15 minutes and then heated under reflux for 1 hour. An excess of aqueous 2N HCl was added to the cooled reaction mixture which was evaporated to dryness. The residue was made basic by the addition of aqueous potassium carbonate solution and this was extracted with diethyl ether (50 mL). The ether extract was washed with brine and dried over MgSO4. The oil obtained on removal of the solvent was subjected to chromatography on silica eluting with dichloromethane to give ethyl 4-[N-(3-benzyloxy-2-thienylmethyl)-N-(ethyl)amino]benzoate as an oil in 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][NH:13][C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:28])[C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1[nH]nc2c1C(c1ccc(Cl)cc1)N(c1ccc(=O)n(C)c1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2c(nn1C)C(=O)N(c1ccc(=O)n(C)c1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-3-methyl-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Example 2) (25 mg, 0.070 mmol) in DMF (1 mL) under Ar was added NaH (3.38 mg, 0.085 mmol). The reaction mixture was stirred at rt for 30 min and MeI (6.61 μL, 0.106 mmol) was added. After 1 hr at rt, the reaction mixture was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4, and evaporated. The crude material was purified by preparative HPLC (Gilson gx-281; column: Sunfire C18, 30×100 mm, 5 μm; flow: 30 mL/min; gradient: 5% to 100% B in 20 min; A=0.1% TFA in H2O, B=CH3CN; detection: UV) to afford the title product (10 mg, 0.027 mmol, 38% yield). tR: 3.39 min (HPLC 1); tR: 0.74 min (LC-MS 2); ESI-MS: 369 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H) 3.34 (s, 3H) 3.83 (s, 3H) 6.10 (s, 1H) 6.30 (d, J=9.8 Hz, 1H) 7.23 (d, J=8.6 Hz, 2H) 7.35 (d, J=8.6 Hz, 2H) 7.44 (dd, J=9.8, 2.7 Hz, 1H) 7.89 (d, J=2.7 Hz, 1H). In addition to the title compound, a second product was isolated during this purification process and is described in Example 4.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[N:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][CH:11]=1)=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: COC(=O)c1cccc(NC(=O)C(C)CSC(C)=O)n1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Product: CC(CS)C(=O)Nc1cccc(C(=O)O)n1

Procedure:
Following the procedure of Example 3, but substituting an equivalent amount of methyl 6-(2-acetylthiomethyl-propionamido)-picolinate, obtained as disclosed in Example 9, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate, 6-(2-mercaptomethyl-propionamido)-picolinic acid is obtained; m.p. 178°-179° C., from acetone/ethyl acetate.
Reaction SMILES: CN(C)[CH:3]=[O:4].[O:6]=[C:7]([CH3:14])[CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].C(=O)([O-])[O-].[K+].[K+].CI>O>[O:6]=[C:7]([CH3:14])[CH2:8][CH2:9][CH2:10][C:11]([O:4][CH3:3])=[O:12]
Reactant: CC(=O)CCCC(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)CCCC(C)=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 80 ml of N,N-dimethylformamide, 25 g (0.19 mol) of 5-oxohexanoic acid and 43 g (0.31 mol) of potassium carbonate were dissolved and heated at 50° C., followed by drop-wisely adding 41 g (0.29 mol) of methyl iodide and stirring at the same temperature for 2 hours. To this mixture, 150 ml of water was added, followed by extracting with diethyl ether (200 ml×4). The organic layer was washed with a saturated saline solution, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 24.9 g (yield: 90%) of methyl 5-oxohexanoate.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:14][O:15][C:16]1([O:33][CH3:34])[C@H:29]([OH:30])[C:28]2[C:19](=[CH:20][N:21]=[C:22]3[C:27]=2[CH:26]=[C:25]([OH:31])[CH:24]=[CH:23]3)[C@@H:18]([CH3:32])[CH2:17]1>CN(C)C=O>[O:31]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[C:28]3[C:19](=[CH:20][N:21]=2)[C@@H:18]([CH3:32])[CH2:17][C:16]([O:15][CH3:14])([O:33][CH3:34])[C@@H:29]3[OH:30])[CH:26]=1)[Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC1(OC)C[C@H](C)c2cnc3ccc(O)cc3c2[C@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC1(OC)C[C@H](C)c2cnc3ccc(O[Si](C)(C)C(C)(C)C)cc3c2[C@H]1O
Temperature: 23 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Imidazole (1.01 g, 14.8 mmol, 2.60 equiv) and t-butyldimethylsilyl chloride (1.11 g, 7.39 mmol, 1.30 equiv) were added sequentially to a solution of (7S,10R)-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-2,10-phenanthridinediol (16, 1.64 g, 5.69 mmol, 1 equiv) in N,N-dimethylformamide (10 mL) at 23° C. After stirring for 1 h at 23° C., the reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was separated and extracted further with two 100-mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by flash column chromatography (30% ethyl acetate-hexanes) to afford (7S,10R)-2-(tert-butyldimethylsiloxy)-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-10-phenanthridinol (17) as a light yellow foam (2.10 g, 91%). ##STR27##
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OC[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.C(O)(=O)C(O)=O.[CH2:56]1C2(CNC2)[CH2:58][O:57]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][C:26]3([CH2:58][O:57][CH2:56]3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C1NCC12COC2
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-6-azaspiro[3.3]heptane oxalate and isolated as white solid (10.8 mg, 57%). MS(m/e): 399.4 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([SH:13])[N:6]=1.Cl[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>O.C(O)C>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([S:13][C:15]2[S:16][CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[N:8]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: O=[N+]([O-])c1ccsc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(Sc2sccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
Sodium hydroxide (1.2 g) was dissolved in water (50 ml), 4,6-dimethoxy-2-mercaptopyrimidine (5.3 g) was added, and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-3-nitrothiophene (5.0 g) dissolved in ethanol (50 ml) was added with stirring, the mixture being stirred at room temperature for 6 hours. The resulting precipitate was filtered, washed with water and dried, to give 7.6 g of the desired product, mp 199°-201° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[C:33]([F:41])[C:34]([C:37]([O:39]C)=[O:38])=[N:35][CH:36]=1)[CH2:22][CH3:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[C:33]([F:41])[C:34]([C:37]([OH:39])=[O:38])=[N:35][CH:36]=1)[CH2:22][CH3:23])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1cnc(C(=O)OC)c(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1cnc(C(=O)O)c(F)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a tetrahydrofuran solution (7.0 ml) of methyl 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-ethylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylate (440 mg) was added at room temperature 1 N aqueous sodium hydroxide solution (1.69 ml), followed by stirring for 2 hours. The reaction solution was poured into a 10% aqueous citric acid solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-ethylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylic acid (429 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:22]=3[N:23]2[S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:19][CH:18]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:22]=4[N:23]3[S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(OCc6ccccc6)cc5=O)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 135 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
A suspension of 4-(benzyloxy)pyridin-2(1H)-one (426 mg, 2.12 mmol), tert-butyl 7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.28 g, 2.54 mmol), CuI (484 mg, 2.54 mmol), 8-hydroxyquinoline (369 mg, 2.54 mmol) and Cs2CO3 (760 mg, 2.33 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135° C. with stirring for 1.5 h. The suspension was cooled, 4:1 CH2Cl2/(9:1 MeOH/NH4OH) (50 mL) was added and the resulting suspension was stirred at 25° C. for 10 min. The suspension was passed through a plug of silica gel and the filtrate was washed with brine. The solution was dried over Na2SO4 and concentrated under reduced pressure to afford an amorphous solid. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH) 100:0 to 0:100) yielded the title compound (715 mg, 54%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.18 (br s, 1H), 7.82-7.73 (m, 2H), 7.48-7.35 (m, 6H), 7.33-7.23 (m, 4H), 6.12-5.97 (m, 2H) 5.07 (s, 2H), 4.90 (br s, 2H), 3.72-3.64 (m, 2H), 2.73-2.63 (m, 2H), 2.34 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11]NC(=O)CCC(N)=O>>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: NC(=O)CCC(=O)NBr
Product: O=[N+]([O-])c1ccccc1CBr

Procedure:
1-Methyl-2-nitro-benzene was reacted with N-bromosuccinamide as described in the synthesis of Example 1e to obtain the title compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[CH:13][C:14]=1Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]1>CN(C=O)C.O>[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[CH:13][C:14]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: CC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Triethylamine (2.2 g, 20.0 mmol), 3,4,6-trichloro-pyridazine (1.8 g, 10.0 mmol) and 1-(piperidin-4-yl)ethanone (1.3 g, 10.0 mmol) was dissolved in DMF (20 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in hexanes) to give 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol, 39% yield) as white solid. ESI-MS (M+1): 274 calc. for C11H13ClN3O 273.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]=[C:10]=S)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To 3,5-dichloro-2-isothiocyanatopyridine (0.11 g, 0.55 mmol) in N,N-dimethylformamide (10 mL) was added Et3N (0.17 mL, 1.21 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.13 g, 0.56 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (10 mL) and N,N′-diisopropylcarbodiimide (0.26 mL, 1.65 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(3,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.08 g, 0.24 mmol, 44% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.91 (s, 1H), 8.11-8.17 (m, 1H), 7.97 (d, J=2.44 Hz, 1H), 3.84 (d, J=9.77 Hz, 1H), 3.59 (d, J=9.77 Hz, 1H), 2.95-3.04 (m, 2H), 2.72-2.81 (m, 2H), 2.66 (t, J=7.63 Hz, 2H), 2.01 (s, 1H), 1.89 (s, 1H), 1.54-1.62 (m, 2H), 1.42-1.50 (m, 1H). MS (LC/MS) R.T.=0.78; [M+]+=326.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Product: ON=Cc1ccc(F)cc1

Procedure:
In another embodiment, 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanol and 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone may be produced as described in Scheme 12A. 4-Fluoro-benzaldehyde is reacted with hydroxylamine hydrochloride to provide 4-fluorobenzaldehyde oxime. The isoxazole ring is then generated by reacting this intermediate with but-3-yn-2-ol and NCS to provide 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol. 1-(3-(4-Fluorophenyl)isoxazol-5-yl)ethanol is then oxidized to the ketone, i.e., 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone, which may then be converted to a compound of formula (I-A) by the methods described herein.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH2:67][C:68]([OH:70])=O)[C:56]([CH3:71])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[NH2:7][C:68](=[O:70])[CH2:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[CH2:60][CH2:59][C:57]1[C:56]([CH3:71])=[CH:55][N:54]=[C:53]([NH:52][C:49]2[CH:50]=[CH:51][C:46]([N:43]3[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:39])[CH2:41][CH2:42]3)=[CH:47][CH:48]=2)[N:58]=1
Reactant: Cc1cnc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HOBt (15 mg, 0.11 mmol), EDCl.HCl (21 mg, 0.11 mmol) and DIPEA (72 μL, 0.41 mmol) were added to a solution of 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetic acid (A9) (44 mg, 0.083 mmol) in dry DMF (10 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (40 mg, 0.41 mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. A solution of HOBt (15 mg, 0.11 mmol), EDCl.HCl (21 mg, 0.11 mmol) and DIPEA in DMF (3 mL) was then added and after 10 minutes ammonium carbonate (40 mg, 0.41 mmol) was added in one portion. The resulting mixture was stirred at 26° C. for a further 24 hours before the volatiles were removed in vacuo and the residue partitioned between EtOAc (65 mL) and saturated NaHCO3 (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL) then the combined organics were washed with brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow solid which was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-100% MeOH in EtOAc). After removing the solvent in vacuo the resulting residue was taken up in EtOAc, filtered through cotton wool and the filtrate evaporated to dryness to give the title compound A10 as a light brown solid (28 mg, 64%); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.47-7.41 (m, 2H), 7.25-7.17 (m, 4H), 7.13 (s, 1H), 6.93-6.88 (m, 2H), 5.59 (s, 1H), 5.53 (s, 1H), 3.65 (s, 2H), 3.61-3.55 (m, 4H), 3.10-3.01 (m, 6H), 2.92-2.88 (m, 2H), 2.08 (s, 3H), 1.48 (s, 9H). LCMS-A: rt 5.525 min; m/z 531.2 [M+H]+
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.45 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-phenethyl-1H-pyridin-2-one (example 18.1a) in 2.0 mL of DCM is added at 0° C. 21 μL (0.23 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is then added to aqueous 5% NaHCO3-solution. The layers are separated, the aqueous phase is extracted with DCM. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.