Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH2:11])[N:10]=[C:4]2[CH:3]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C.CP(C)C.[CH3:31][C:32]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)[S:34][N:33]=1.[B][B][B][B][B][B][B][B][B][B].C([O-])(O)=O.[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][CH:40]3[CH2:39][CH2:38][N:37]([C:35]4[S:34][N:33]=[C:32]([CH3:31])[N:36]=4)[CH2:42][CH2:41]3)[N:10]=[C:4]2[CH:3]=1
Reactant: Nc1nc2cc(Br)ccn2n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Agent: CP(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nsc(N2CCC(Nc3nc4cc(Br)ccn4n3)CC2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-b starting from 4-bromo-pyridin-2-ylamine) (250 mg, 1.17 mmol) and hexachloroethane (333 mg, 1.41 mmol) under argon in dry THF (12.5 mL) was added triethylamine (356 mg, 491 μL, 3.52 mmol) and the mixture was heated to 50° C. for 10 minutes. Trimethylphosphine (1 M in THF, 1.41 mL, 1.41 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h, then 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (278 mg, 1.41 mmol) was added and the mixture heated in the microwave to 150° C. for 30 minutes. To the reaction mixture a solution of decaborane (143 mg, 153 μL, 1.17 mmol) in dry methanol (3 mL) was added and stirred at for 3 hours at room temperature. Further decaborane (34.4 mg, 36.6 μL, 282 μmol) in dry methanol (1.00 mL) was added. The reaction mixture was heated to 60° C. for 12 hours. Further decaborane (17 mg) dissolved in methanol (1 mL) was added and heated to 70° C. for 3 hours. Aqueous NaHCO3 solution was added and the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as off-white solid (300 mg, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]1([N:23]2[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:18]1([N:23]2[CH2:28][CH2:27][CH:26]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CS(=O)(=O)OC1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OC3CCN(C4CCCC4)CC3)cc2)CCOCC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (459 mg, 2.26 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester (447 mg, 1.81 mmol) in DMF (1.3 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by successive column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a pale yellow solid (81 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.93 (d, 2H), 4.36 (m, 1H), 4.11-4.04 (m, 2H), 3.89 (td, 2H), 2.91-2.77 (m, 2H), 2.67-2.25 (m, 2H), 2.15-1.99 (m, 7H), 1.95-1.81 (m, 4H), 1.78-1.64 (m, 2H), 1.62-1.39 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[O:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:25](O)=[O:26])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[O:15]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:25]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)=[O:26])[CH2:18][CH2:17]2)[O:12][CH2:13][CH2:14]1
Reactant: Cc1ccc(C(=O)O)cc1N1CCC2(CC1)OCCO2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of 3-Trifluoromethyl-phenylamine (24.1 mg, 0.15 mmol), 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-benzoic acid [as prepared in reference 3] (41.5 mg, 0.15, and DIPEA (78 μl, 0.45 mmol) in DMF was added HATU (59 mg, 0.15 mmol), and the reaction mixture was stirred for 3 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 43.1 mg (68.6%) of 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide [25] as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17]([O:32][CH3:33])(=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O-])=[O:29]>>[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:29])([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Reactant: CCOC(=O)CCCOc1cccnc1N
Product: CCOC(=O)CCCOc1cccnc1NC(=O)CCCCCCCCCCC(=O)OC

Procedure:
When (41) and (7) are reacted as per the procedure of step (E), above, the title compound (42) is obtained. Hydrolysis will yield the corresponding di-acid (4-(2-(11- Carboxyundecanoylamino)pyrid-3-yloxy)butyric acid (43).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCOc3cc([N+](=O)[O-])ccc32)c1
Yield: 102.5 %

Procedure:
The same operation as in Example (90a) was performed using 7-nitro-2,3-dihydro-4H-1,4-benzoxazine (described in Higuchi, Robert I.; Arienti, Kristen L.; Lopez, Francisco J.; Mani, Neelakhanda S.; Mais, Dale E.; Caferro, Thomas R.; Long, Yun Oliver; Jones, Todd K.; Edwards, James P.; Zhi, Lin; Schrader, William T.; et al.; J. Med. Chem.; 50; 10; 2007; 2486-2496, 0.6 g, 3.3 mmol), sodium hydride (55% content, 145 mg, 3.3 mmol), methyl 3-bromomethylbenzoate (0.76 g, 3.3 mmol) and DMF (50 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) gave 1.11 g of the title compound as a deep yellow solid (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH2:15][Br:23])=[CH:9][CH:8]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)c1cc(Br)ccc1n2C(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc(CBr)ccc21
Yield: 69.6 %

Procedure:
A suspension of 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole obtained from Example 25 (653 mg, 1.81 mmol) and recrystallised N-bromosuccinimide (355 mg, 2.00 mmol) in carbon tetrachloride was refluxed under nitrogen with irradiation from a 150W halogen lamp for 2.5 h. The reaction mixture was cooled over an ice bath and filtered, and the filtrate evaporated. The crude product was chromatographed (PS with gradient elution to PS:DCM 1:1) to afford 3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole (551 mg, 1.26 mmol, 69%) as a colourless solid, mp 150° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].Br[CH2:19][C:20]1[C:21]([Cl:26])=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:19][C:20]3[C:21]([Cl:26])=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: Clc1ncccc1CBr
Product: CCOC(=O)c1cc(-c2ccc(OCc3cccnc3Cl)cc2)no1

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 1) and 3-bromomethyl-2-chloro-pyridine (which may be prepared as described in Selby, T. P. and Winters, M. P. U.S. Pat. No. 5,739,326 Column 19) were reacted using conditions similar to those described for Preparation of Intermediate 24 to give 3-[4-(2-chloro-pyridin-3-ylmethoxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33]N=[CH:31][N:30]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)[CH:11]=1)(=[O:9])=[O:8].[CH3:40]OC1C=C(OC)C=CC=1CNC1SC=CN=1.COC1C=C(OC)C=CC=1CNC1SN=CN=1>>[CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][CH:40]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[B:20]2[O:21][C:22]([CH3:27])([CH3:28])[C:23]([CH3:26])([CH3:25])[O:24]2)[CH:11]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cccc3c2)c(OC)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: COc1ccc(CNc2ncns2)c(OC)c1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cccc3c2)c(OC)c1

Procedure:
Intermediate II was synthesized in a similar manner to Intermediate E, using N-(2,4-dimethoxybenzyl)thiazol-2-amine instead of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Intermediate A) in Step 3, to yield N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as a white solid. m/z (ESI) 567.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][N:5]2[C:6]3[C:11]([NH:12][C:13](=O)[CH:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[NH4+].C(O)(=O)/C=C/C(O)=O>CC(C)=O.O1CCCC1>[CH3:1][N:2]1[CH2:16][CH2:15][N:5]2[C:6]3[C:11]([NH:12][CH2:13][CH:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CN1CCN2c3ccccc3NC(=O)C2C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN1CCN2c3ccccc3NCC2C1

Procedure:
A mixture of 7.1 g. of 2,3,4,4a-tetrahydro-3-methyl- 1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 3.5 g. of lithium aluminum hydride and 450 ml. of dry tetrahydrofuran is refluxed for 20 hours under a nitrogen atmosphere. The mixture is cooled and 20 ml. of concentrated ammonium hydroxide is carefully added. The mixture is filtered and the filter cake is washed with isopropanol. The filtrate is concentrated to give 5.7 g. of product as a viscous oil. A 3.5 g. portion is dissolved in acetone and treated with a saturated solution of fumaric acid in acetone. Filtration gives 3.3 g. of the product as the fumaric acid salt, m.p. 178°-188°. Recrystallization from isopropanol gives 2.1 g. of salt, m.p. 186°-188° .
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:21]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[Cl-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:21])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (5.0 mg) in N,N-dimethylformamide (0.1 mL) were added 1-hydroxybenzotriazole (3.9 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 mg). The mixture was stirred at 60° C. for 30 minutes. To the solution was added ammonium chloride and the mixture was stirred at ambient temperature for 18 hours. To the solution were added water and chloroform and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtrated and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (3 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]12[CH2:37][CH:5]([C:6]3([CH3:36])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:35])[CH2:17][O:18][C:19]4[CH:34]=[CH:33][C:22]([C:23]([O:25]CC5C=CC=CC=5)=[O:24])=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]12[CH2:37][CH:5]([C:6]3([CH3:36])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:35])[CH2:17][O:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:33][CH:34]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(=O)COc4ccc(C(=O)OCc5ccccc5)cc4)cc3C21C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)COc4ccc(C(=O)O)cc4)cc3C21C
Yield: 73.5 %

Procedure:
4.41 g (8.8 mmol) of the benzyl ester obtained in step (a) in 70 ml of dioxane were hydrogenated in the presence of 132 mg of palladium (10%) on charcoal at 60° C. at a hydrogen pressure of 7 bars for 8 hours. After filtration of the reaction medium through Celite and evaporation, the residue was chromatographed on silica in the eluent CH2Cl2 /ethyl ether (95:5). After the product was converted into a paste in hexane, 2.63 g (73%) of the expected compound, melting at 187.5° C., were isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: Fc1ccccc1OCCCCl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(3-chloropropoxy)-2-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([O:15][C:16](=[O:23])/[CH:17]=[CH:18]/[C:19]([F:22])([F:21])[F:20])[CH3:14]>>[CH:10]([C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:23])[CH:18]([C:19]([F:20])([F:22])[F:21])[O:1]2)=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: CC(C)c1ccc(C=O)c(O)c1
Product: CCOC(=O)C1=Cc2ccc(C(C)C)cc2OC1C(F)(F)F

Procedure:
This salicylaldehyde (Step 1) was condensed with Ethyl-4,4,4-triflurocrotonate via a similar method to that of Example 4a, Step 1 producing the ethyl ester (8.21 g, 84%) as yellow solid. This ester was of suitable purity to use without further purification: ESLRMS m/z 315 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[CH:21]=O>C(O)C.Cl.C(O)(C)C.O>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:21][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=2)=[O:10])[CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(Cl)c(O)c(OC)c2)cc1-c1ccccc1
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A solution of 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (200 mg, 0.869 mmol) and 3-chloro-4-hydroxy-5-methoxybenzaldehyde (194 mg, 1.04 mmol) in ethanol (2 mL) and 5 N HCl in isopropanol (1 mL) is stirred at rt for 18 h. The dark green solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (5 mL) and THF (5 mL) and treated with Pd/C (150 mg, 10% Pd). The slurry is hydrogenated under 1.8 bar of H2 for 18 h. The mixture is filtered over celite, the solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (208 mg) as a colourless oil; LC-MS: tR=1.10 min, [M+1]+=401.12; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.46-7.30 (m, 5H), 6.83 (d, J=1.8 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 3.88 (s, 3H), 3.16 (t, J=7.6 Hz, 2H), 2.98 (t, J=7.6 Hz, 2H), 2.91 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([OH:28])[CH3:27])[CH:21]=3)[N:14]=2)=[CH:11][CH:10]=[N:9]1>ClCCl.[O-2].[O-2].[Mn+4]>[C:26]([C:22]1[CH:21]=[C:20]([N:15]2[CH:16]=[CH:17][C:18](=[O:19])[C:13]([C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[CH:10][CH:11]=3)=[N:14]2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])[CH3:27]
Reactant: CC(O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[2-(2-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-[3-(1-hydroxy-ethyl)-phenyl]-1H-pyridazin-4-one (example 298) by treatment with manganese dioxide in dichloromethane at room temperature for 6 h. MS: M=375.1 (M+H)+
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29]>C1COCC1>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: C=CCCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
In a 250 mL round-bottomed flask was (S)-4-benzyloxazolidin-2-one (5 g, 28.2 mmol) and THF (30 mL) to give a colorless solution. Cooled in −78° C. bath. 2.5M BuLi in hexane (11.29 mL, 28.2 mmol) was added slowly to the oxazolidinone. Initially a thick white precipitate formed, added another 10 mL THF. At the end of the addition the reaction mixture became light orange and contained white solid material. The reaction mixture was stirred at −78° C. for 1 h, and then pent-4-enoyl chloride (3.11 mL, 28.2 mmol) was added dropwise to the oxazolidinone anion at −78° C. The orange color immediately discharged and the reaction became a pale yellow color. Still several large white chunks in the reaction. After 30 min. The reaction mixture was removed from −78° C. bath and let warm to room temperature. All the white chunks have dissolved. The reaction mixture was then stirred at room temperature for 4 h. The reaction was quenched with saturated NH4Cl. The reaction mixture was diluted with 10% aqueous LiCl and Et2O. The organic layer was separated and washed with saturated aqueous NaHCO3 and then washed with brine. The organic layer was dried over MgSO4, filtered and concentrated to give a crude material. This crude material was purified on silica gel column (120 g ISCO) eluting with a gradient from 100% hexane/EtOAc to 50% hexane/EtOAc. The product came off ˜20% EtOAc/hexane. The product was collected in tubes and concentrated to afford (S)-4-benzyl-3-(pent-4-enoyl)oxazolidin-2-one, Intermediate S8A (4.35 g, 16.78 mmol, 59.5% yield) as thick colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.43-7.22 (m, 5H), 6.01-5.81 (m, 1H), 5.20-5.02 (m, 2H), 4.78-4.62 (m, 1H), 4.29-4.16 (m, 2H), 3.34 (dd, J=13.4, 3.3 Hz, 1H), 3.19-3.02 (m, 2H), 2.80 (dd, J=13.3, 9.6 Hz, 1H), 2.50 (d, J=7.3 Hz, 2H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([NH2:15])[CH:12]=[N:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH3:22][N:23](C)[CH:24]=[O:25]>>[CH:22]1([NH:23][C:24]([NH:15][C:13]2[CH:12]=[N:11][C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)[N:14]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:9]1
Reactant: CN(C)C=O
Reactant: Nc1cnc(-c2ccncc2)c(-c2ccccn2)n1
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2ccccn2)n1)NC1CCCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Sodium hydride (17 mg, 0.43 mmol) in anhydrous dimethylformamide (3.5 mL) was stirred at 0° C. under nitrogen atmosphere. 6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine (Example 12, 90 mg, 0.36 mmol) in anhydrous dimethylformamide (2.5 mL) and cyclopentylisocianate (50 μL, 0.43 mmol) were sequentially added. The mixture was stirred at 70° C. under nitrogen atmosphere for 1 h 30 min. Dimethylformamide was removed in vacuo and the resulting solid was triturated with hexanes-dichloromethane, filtered, washed with hexanes and dried. Silica gel flash chromatography of the solid (dichloromethane to dichloromethane/methanol 95:5) afforded the title compound (53 mg, 41%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]1[NH:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[C:7]1=[O:21].Cl[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO.O>[CH3:26][O:25][C:23]([NH:2][CH2:3][CH2:4][CH2:5][C@@H:6]1[NH:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[C:7]1=[O:21])=[O:24]
Reactant: COC(=O)Cl
Reactant: NCCC[C@@H]1NC(=O)N(c2cccc(C(=O)O)c2)C1=O
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)NCCC[C@@H]1NC(=O)N(c2cccc(C(=O)O)c2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
314 mg (1 mmol) of 3-(5-(S)-(3-aminopropyl)-2,4-dioxoimidazolidin-3-yl)-benzoic acid hydrochloride are dissolved in 5 ml of methanol and 5 ml of water. After addition of 130 mg (1.38 mmol) of methyl chloroformate, the mixture is adjusted to pH 7 at 10° C. with 0.1 N sodium hydroxide solution. The mixture is allowed to warm to room temperature, and is stirred for 4 h, acidified to pH 3 with potassium hydrogen sulphate solution and concentrated. The residue is stirred with water, filtered off with suction and dried.