Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:20])([CH3:21])[C:17](=[O:22])[C:16]=2[Br:30])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=CC1=O
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a room temperature solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethylfuran-3(2H)-one (1.5 g, 0.005 mol) in CHCl3 (50 mL), NBS (1.37 g, 0.007 mol) was added portionwise. The reaction mixture was stirred for 2 h at RT and then concentrated in vacuo to obtain the crude product. The residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated in vacuo to afford 5-(4-(benzyloxy)phenyl)-4-bromo-2,2-dimethylfuran-3(2H)-one (2.0 g) as a solid. This material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=2)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:38])=[CH:21][N:20]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=5)[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C:22]([CH3:38])=[CH:21][N:20]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1cnc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (91 mg, 0.35 mmol) and tert-butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoate (50 mg, 0.175 mmol), pyridine (2 mL) was added. The reaction was heated at 90° C. for twenty four hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in ethyl acetate and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate. ESI-MS m/z calc. 509.18. Found 510.5 (M+1)+. Retention time 2.22 minutes
Reaction SMILES: Cl[C:2]1(Cl)[CH2:7][O:6][CH2:5][CH2:4][O:3]1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[NH2:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:2][CH2:7][O:6][CH2:5][C:4]2=[O:3])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: ClC1(Cl)COCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 66 h
Yield: 83 %

Procedure:
12.8 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) are added to a solution of 10.0 g (65.7 mmol) of 3-methyl-4-nitroaniline in 250 ml of acetonitrile, and the mixture is stirred at 80° C. for 66 hours. The reaction solution is cooled to room temperature, 42.8 g (131 mmol) of caesium carbonate are added, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered, the residue is washed well with acetonitrile, and the filtrate is evaporated. The residue is recrystallised from a little acetonitrile, giving 12.8 g (83%) of 4-(3-methyl-4-nitrophenyl)morpholin-3-one as yellowish solid. ESI 236. 1H-NMR (d6-DMSO): δ=2.54 (s; 2H), δ=3.82 (t, J=5 Hz; 2H), 4.00 (t, J=5 Hz; 2H), 4.25 (s; 2H), 7.57 (m; 2H), 8.04 (d, J.=8 Hz; 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)S(O[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.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>[Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cccc(Cl)c1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(Cl)c2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 59.9 %

Procedure:
A mixture of (3-chloro-2-(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2-dimethoxyethane (10 mL) was heated at 80° C. under microwave irradiation for 1 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as colorless oil (0.438 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.44-7.34 (m, 2H), 7.09 (m, 1H), 5.49 (br, 1H), 4.01 (br, 2H), 3.60 (br, 2H), 2.30 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N)c(OC)c1
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a stirred solution of ethyl 2-(3-methoxy-4-nitrophenyl)propanoate (683 mg, 2.697 mmol) in tetrahydrofuran and ethanol as co-solvent were added 10% Pd/C (70 mg). The mixture was charged with H2 (gas) balloon. The resulting mixture was stirred for 15 h, then filtered using celite. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(4-amino-3-methoxyphenyl)propanoate (447 mg) was obtained as 74% yield.
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=O.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[N+:18]([C:16]1[CH:15]=[N:14][N:13]([CH2:12][C:9]2[O:8][C:7]([CH2:5][OH:4])=[CH:11][CH:10]=2)[CH:17]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(Cc2ccc(CO)o2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-pyrazol-1-ylmethyl)-furan-2-carboxylic acid methyl ester (10.0 g, 39.81 mmol) in THF (300.0 mL) was treated dropwise, at −78° C. with DiBAL (160.0 mL of a 1M solution in toluene, 160.0 mmol). The reaction mixture was stirred at −78° C. for 1.5 h and at rt for 1 h. Sat. aq. Rochelle's salt (600 mL) was added and the reaction mixture was stirred at rt for 1 h. The aq. layer was extracted with EA (2×350 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA) gave the title compound. TLC: rf (40:60 hept-EA)=0.28. LC-MS-conditions 02: tR=0.74 min. 1H NMR (400 MHz, CDCl3) δ 2.10 (s, 1H), 4.62 (s, 2H), 5.31 (s, 2H), 6.33 (d, J=3.0 Hz, 1H), 6.47 (d, J=3.0 Hz, 1H), 8.08 (s, 1H), 8.15 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10](C3C=CC(Cl)=CC=3)=[C:9]([O:18][CH3:19])[C:8]([CH3:20])=[CH:7][C:5]=2[N:6]=1.[CH3:21][NH:22][CH3:23].C1COCC1>CN(C=O)C>[CH3:19][O:18][C:9]1[C:8]([CH3:20])=[CH:7][C:5]2[N:6]=[C:2]([N:22]([CH3:23])[CH3:21])[S:3][C:4]=2[CH:10]=1
Reactant: CNC
Reactant: COc1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2sc(N(C)C)nc2cc1C
Temperature: 80 °C

Procedure:
To a solution of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C) (135 mg, 0.37 mmol) in DMF (2 ml), was added dimethylamine in THF (2M, 0.46 ml, 0.92 mmol). The reaction mixture was stirred at 80° C. After the reaction finished, the reaction was cooled and concentrated. The residue was purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI+: calc'd for C17H17ClN2OS: 333.1 (M+H+). Found: 333.1 (M+H+).
Reaction SMILES: [O:1]1CC(=O)N=N1.C(OC(=O)CCN[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][O:23][C:24](=[O:26])[N:25]=2)=[CH:17][CH:16]=1)C.O.[OH-].[Na+]>C1COCC1.CO>[O:23]1[C:24](=[O:26])[N:25]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([OH:27])=[O:1])=[CH:20][CH:19]=2)[NH:22]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Reactant: O=C1CON=N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(=O)o[nH]2)cc1
Yield: 97 %

Procedure:
p-Cyanobenoic acid methyl ester (5.0 g, 31 mmol) was converted into the corresponding oxadiazolinone as described for the synthesis of compound 3. The crude product (4.6 g, 20.9 mmol) was dissolved in a mixture of THF (50 mL) and MeOH (50 mL). H2O (50 mL) was added, which gave a suspension, followed by 4 N aq. NaOH (10 mL). After 6 h the organic solvents were removed by distillation under reduced pressure. The aq. layer was extracted with EtOAc/toluene (1/2, v/v), acidified with 2 N hydrochloric acid and the precipitate was filtered off. The crude product was dried at 40° C. under reduced pressure to give 4.2 g (97%) of compound 60. ESI-MS: 207 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:16])=[C:10]([CH2:12][C:13]([OH:15])=O)[CH:11]=1.Cl.[NH2:18][C:19]1([C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:16])=[C:10]([CH2:12][C:13]([NH:18][C:19]2([C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]2)=[O:15])[CH:11]=1
Reactant: Cc1ccc(Br)cc1CC(=O)O
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(F)(F)CC1
Temperature: 80 °C

Procedure:
36.5 ml (500 mmol) of thionyl chloride were added to 22.91 g (100 mmol) of (5-bromo-2-methylphenyl)acetic acid (EP 1791816 A1 and WO 2006/29799 A1), and the mixture was stirred at 80° C. until the evolution of gas was complete and then concentrated. The residue was dissolved in 100 ml of tetrahydrofuran (THF) (solution A). 25.3 g (110 mmol) of the compound from Example 4A were initally charged in 308 ml of THF, 21.3 ml of triethylamine were added dropwise at 20° C., solution A was then added dropwise with cooling and the mixture was stirred at room temperature until the reaction had gone to completion. The precipitate is filtered off with suction and washed with THF, the filtrate is concentrated under reduced pressure and the residue is recrystallized from methyl tert-butyl ether. This gave 33.6 g (83% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH3:36].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:34][CH2:35][CH3:36])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A suspension of 0.50 g of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5, potassium carbonate (0.76 g), and 1-iodopropane (0.47 g) in DMF is heated to 100° C. for 6 hrs and stirred at room temperature overnight. The reaction mixture is filtered, and the solvent is evaporated at reduced pressure leaving a light brown solid. The solid is stirred with ethyl acetate for an hour and filtered. The solvent is evaporated from the filtrate under reduced pressure, leaving 0.12 g of the title compound as a yellowish-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20]>CN(C1C=CN=CC=1)C.ClCCl>[C:19](=[O:20])([O:21][CH3:22])[O:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: COC(=O)Cl
Reactant: CCc1cc(F)ccc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(F)ccc1OC(=O)OC
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2-Ethyl-4-fluorophenol (2 g, 14.27 mmol) and DMAP (87 mg, 0.71 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (4 mL, 28.5 mmol), cooled to 0° C., then treated with methyl chloroformate (2.02 g, 1.65 mL, 21.40 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water, the layers separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (20% ethyl acetate/hexane) provided 2-ethyl-4-fluorophenyl methyl carbonate (2.4 g, 85% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.26-7.17 (m, 2H), 7.12-7.07 (m, 1H), 5.76 (s, 1H), 3.83 (d, J=4.3 Hz, 2H), 2.54-2.48 (m, 2H), 1.12 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:15])=O>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]([Cl:15])=[O:12])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ncc(Cl)c(C(=O)Cl)n1
Yield: 91.7 %

Procedure:
With stirring, 15 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid were added a little at a time to 40.8 g (25 ml, 0.34 mol) of thionyl chloride and 0.47 g (0.5 ml, 6.5 mmol) of N,N-dimethylformamide, and the reaction mixture was then heated under reflux until a marked evolution of gas was no longer noticeable. The mixture is taken up in a little methylene chloride. Concentration gives 15 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carbonyl chloride, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16](OC)[O:17]C)[CH:13]=2)=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1.O>C1COCC1>[F:1][C:2]1[C:7]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16]=[O:17])[CH:13]=2)=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1
Reactant: COC(CCn1cc(-c2cc(C)cnc2F)c(=O)[nH]c1=O)OC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(F)c(-c2cn(CCC=O)c(=O)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
5-(2-Fluoro-5-methyl-pyridin-3-yl)-1-(3,3-dimethoxy-propyl)-1H-pyrimidine-2,4-dione (Prep100, 200 mg, 0.62 mmol) was dissolved in THF (5 ml) and 2N HClaq (1 ml) was added. The solution was stirred at room temperature for 3 hours. The reaction mixture was neutralized with TEA (278 μl, 2 mmol). Water was added and the product extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated to give 150 mg of a colorless oil (88% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=O)=[CH:6][CH:5]=1.I.CS[C:19](=[NH:28])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]2[NH:28][C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CSC(=N)Nc1ccc(O)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(Nc2nnc(-c3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
4-trifluoromethoxybenzoic acid hydrazide (1.1 g, 5.0 mmol) and S-methyl N-[4-hydroxy-phenyl]isothiourea hydroiodide (1.55 g, 5.0 mmol) were suspended in 10 mL of anhydrous pyridine. The reaction mixture was refluxed for 24 hours, during which time it changed color from yellow into orange-red. Then it was cooled down to ambient temperature and poured with stirring into 150 mL of ice-water. The aqueous layer was decanted and the resulting residue was purified by silica gel chromatography using 1:1 mixture of ethyl acetate/hexane. Solvent was removed in vacuo to give the title product as a pinkish-grey solid (684.0 mg). 40.6% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[CH2:34]([CH2:36][NH2:37])[OH:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:35][CH2:34][CH2:36][NH:37][C:21]([C:5]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1)=[O:22]
Reactant: NCCO
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NCCO)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with ethanolamine, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 505.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24]O)=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24][Br:27])=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CCO)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CCBr)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
To a stirred solution of 7-tert-butoxycarbonyl-2-[4-(2-hydroxyethyl)-2-methoxy-5-pyridinyl]-7-azabicyclo[2.2.1]hept-2-ene (390 mg, 1.13 mmol) in dry CH2Cl2 (20 mL) under N2 was added CBr4 (745 mg, 2.25 mmol). The mixture was stirred at room temperature for 10 min, and then a solution of PPh3 (590 mg, 2.25 mmol) in dry CH2Cl2 (5 mL) was slowly added. After that the reaction mixture was stirred at room temperature for 2 h and quenched by water, and then diluted with CH2Cl2. The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (6:1) to afford 7-tert-butoxycarbonyl-2-[4-(2-bromoethyl)-2-methoxy-5-pyridinyl]-7-azabicyclo[2.2.1]hept-2-ene as a syrup (400 mg, 87%). 1H NMR (CDCl3) δ 7.95 (br s, 1H), 6.66 (s, 1H), 6.23 (br s, 1H), 4.86 (d, 1H, J=3.6 Hz), 4.81 (br s, 1H), 3.94 (s, 3H), 3.59-3.46 (m, 2H), 3.42-3.12 (m, 2H), 2.09-1.92 (m, 2H), 1.45 (s, 9H), 1.36-1.20 (m, 2H); 13C NMR (CDCl3) δ 163.83, 155.35, 148.55, 146.16, 144.63, 132.04, 123.16, 111.15, 80.16, 63.16, 61.35, 53.44, 35.97, 30.76, 28.20, 25.96 and 25.32, 24.55 and 23.62.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26]CCC)=[CH:21][CH:20]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([N:1]2[CH2:4][CH:3]([CH:5]([C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: CCCCC(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(C)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.015 g (0.054 mmole) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate, 0.020 g (0.101 mmol) of 1-(4-chlorophenyl)pentan-1-one and 0.015 mL (0.12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.050 g (0.237 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 6 h. The reaction was quenched by addition of saturated K2CO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound as a mixture of isomers; Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][CH:19]=[C:20](C)[C:21]=2[Br:22])=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(N1CCC(C(C2SC(C)=CC=2Br)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][C:19]([CH3:24])=[CH:20][C:21]=2[Br:22])=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1csc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Reactant: Cc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Product: Cc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Prepared essentially as 29b except that 4-[1-(3-Bromo-5-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester is used as the starting material and the reaction mixture was stirred at 70° C. for 6 hours. LC/MS (ESI), m/e 347 (M-56) and 403 (MH+), retention time 2.03 minutes. Condition II.