Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:30])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=[O:29])[NH:23][CH2:24][CH:25]([OH:28])CO)[CH2:5]1.O>C1COCC1>[F:30][CH:2]([F:1])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=[O:29])[NH:23][CH2:24][CH:25]=[O:28])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)NCC(O)CO)O2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)NCC=O)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To tert-butyl 4-(2,2-difluoroethyl)-2-((2,3-dihydroxypropyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (422 mg, 0.96 mmol) in THF (10 mL) was added NaIO4 (522 mg, 2.44 mmol) followed by H2O (4 mL) the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and partitioned between sat. aq. sodium bicarbonate/ethyl acetate. The aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, and concentrated in vacuo to yield tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxoethyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (377 mg, 96%) as a white solid, which was taken onto the next step without purification. ESI-MS m/z calc. 405.2. found 406.5 (M+1)+; Retention time: 1.32 minutes (3 min run).
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[NH2:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22]>C(O)C>[C:1]([NH:3][CH:4]=[N:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])#[N:2]
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1N
Reactant: CCOC=NC#N
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N=CNC#N
Temperature: 25 °C
Reaction time: 45 h
Yield: 35.5 %

Procedure:
Ethyl N-cyanoformimidate (3.2 g) was added to a suspension of 3-amino-7-chloro-2-methylimidazo[2,1-a]isoquinoline (2.3 g) in ethanol (60 ml) and the mixture was stirred at room temperature for 45 hours. The mixture was evaporated in vacuo and the residual solid was washed successively with diethyl ether and ethyl acetate to give N-cyano-N'-(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)formamidine (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:13]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: COc1cccc2c1CCC2=O
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2c(OC)cccc2C1=O
Yield: 23 %

Procedure:
A solution of 21.5 g of 4-methoxy-1-indanone, 27.4 ml of 3-buten-2-ol and 210 mg of p-toluenesulfonic acid in 27.4 ml of 2,2-dimethoxypropane and 210 ml of anhydrous toluene was boiled under reflux for 16 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1). 6.42 g (23%) of (RS)-2-(2-buten-1-yl)-4-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Reactant: CCOC(=O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution containing 4,6-dimethyl-2-methylsulfonylpyrimidine (10.0 g, 53.8 mmol), ethyl glycolate (5.60 g, 53.8 mmol), and 30 mL of N,N -dimethylformamide was prepared and to this was added with stirring potassium carbonate (8.0 g, 60 mmol). The mixture was allowed to stir at ambient temperature overnight. It was then poured into water and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were extracted with water. The aqueous extract was saturated with sodium chloride and extracted twice more with ethyl acetate. All of the ethyl acetate layers were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 8.20 g (72.6 percent of theory) of the title compound as a yellow oil. This oil was filtration chromatographed on silica gel, eluting with a 30:70 mixture of ethyl acetate and hexane. The product containing eluate was concentrated by evaporation under reduced pressure to obtain 7.9 g (70 percent of theory) of the title compound as a colorless oil which solidified on standing to a white solid melting at 57°-59° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=2)[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(CCl)cc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)cc3)C2SC1

Procedure:
A mixture of 1 g of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of p-chloromethylphenylacetyl chloride in 45 ml of ethyl acetate is refluxed for about 2 hours after which the solvent is removed under vacuum yielding a yellow-brown amorphous product which is chromatographed on silica gel using benzene-acetone as the eluant to give 3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 164°-165° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29][O:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1cc2ccccc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4cc5ccccc5o4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), 1-benzofuran-2-ylmethanol (58 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (16 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([C:8]([O:10]CC)=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Yield: 90.6 %

Procedure:
A solution of 670 mg (3.2 mmol) of ethyl 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 15) and 3.2 ml (3.2 mmol) 1N NaOH in 20 ml MeOH was heated at 100° C. in a microwave reactor for 2 h. The mixture was diluted with water and extracted with EtOAc. The EtOAc was washed with 1N NaOH. The combined aqueous layers were acidified with concentrated HCl and extracted 2 times with EtOAc, each extract being washed with brine. The combined EtOAc layers were dried over anhydrous MgSO4, filtered and the solvent was removed to give 535 mg of product as a solid. MS (ES) (M−H−): 183 for C7H5ClN2O2; NMR (d6-DMSO): 2.2 (s, 3H), 12.9 (s, 1H), 13.3 (s, 1H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl>[CH:1]1([N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[S:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Fc1cccc(NC2CCC2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)N(c1cccc(F)c1)C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of cyclobutyl-(3-fluoro-phenyl)-amine (447 mg, 2.7 mmol) in DCM (8 mL) was added pyridine (438 μL, 5.4 mmol) followed by 4-fluorobenzenesulfonyl chloride (633 mg, 3.3 mmol) in DCM (3 mL) and then the reaction was stirred at room temperature for 2 hrs. The reaction was left to stand at room temperature for 64 hours. 1 M aqueous HCl was added then extracted with DCM, filtered through a phase separator and then purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give N-cyclobutyl-4-fluoro-N-(3-fluoro-phenyl)-benzenesulfonamide (756 mg, 2.3 mmol, 85%). LCMS (m/z, Method A) ES+ 324 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([O:13]CC)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:16]1[C:17]2=[CH:18][CH:19]=[CH:24][C:23]2=[CH:22][CH:21]=[C:20]1[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1/[CH:8]=[CH:9]/[S:10]([OH:13])(=[O:11])=[O:12]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCOS(=O)(=O)/C=C/c1ccc(Br)cc1
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: CN(C)C=O
Product: O=S(=O)(O)/C=C/c1ccccc1-c1ccc2cccc-2o1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
1-Bromo-4-[(E)-2-ethoxysulfonylethenyl]benzene (1.0 g, 3.4 mmol) and benzofuran-2-boronic acid (0.61 g, 3.7 mmol) were dissolved in DMF (20 mL). Sodium carbonate (2M, 10 mL) and tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) were added and the resulting mixture was stirred under argon at 90° C. for 12 h. Water was added to the mixture and the resulting precipitate was collected, washed with water and dried to give the product as a sodium salt which was used in the next step without further purification (0.38 g, 35%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26]>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][C:22]([O:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24])=[CH:23][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Product: O=S(=O)(Oc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1)C(F)(F)F
Yield: 56 %

Procedure:
The title compound was prepared from 5-methoxy-[2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene in 56% yield for 2 steps via demethylation previously described and triflate formation by a conventional method.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:20][CH3:21])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.Br[CH:23]([CH3:27])[C:24](=O)[CH3:25].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:27][C:23]1[N:1]=[C:2]2[C:10]([O:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]2[C:24]=1[CH3:25]
Reactant: CCc1cccc(C)c1COc1cc(C(N)=O)cnc1N
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1cccc(C)c1COc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 35.1 %

Procedure:
6-amino-5-(2-ethyl-6-methylbenzyloxy)nicotinamide (0.14 g, 0.49 mmol), 3-bromo-2-butanone (0.075 g, 0.49 mmol) and sodium bicarbonate (0.1 g, 1.2 mmol) was added to acetonitrile (3 ml) and was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Crystallization from acetonitrile gave 0.058 g (35%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=O)=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([N:14]2[C:7](=[O:6])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]2=[O:5])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC1=C(C)C(=O)OC1=O
Product: CC1=C(C)C(=O)N(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
In a manner analogous to that of Example 2, 26.2 g (0.2 mole) of dimethylmaleic acid anhydride and 32.6 g (0.2 mole) of 3,4-dichloroaniline are condensed to give N-(3,4-dichlorophenyl)dimethyl-maleimide, which is then dissolved in 300 ml of methanol. To this solution is slowly added in portions, with stirring, 10.8 g of sodium borohydride. After the addition is complete and the generation of gas has subsided, the reaction mixture is poured into ice water. The white precipitate is filtered off, washed with methanol and dried. There is obtained 49.3 g (84% of theory) of the above product in the form of colourless crystalline powder, m.p. 188°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24]>CN(C=O)C>[CH2:7]([O:22][C:20]1[CH:19]=[CH:18][C:17]([C:23](=[O:25])[CH3:24])=[C:16]([OH:15])[CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O
Reaction time: 5 h

Procedure:
Potassium carbonate (54 g, 0.39 mol) followed by benzyl bromide (13.9 mL, 0.12 mol) were added to a solution of 2′,4′-dihydroxyacetophenone (20 g, 0.13 mol) in DMF (180 mL). The mixture was stirred for 5 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, 1 N HCl, brine, dried over Na2SO4 and concentrated to a clear oil (23.7 g, 81%). 1H NMR (400 MHz, CDCl3): δ 2.56 (s, 3H), 5.02 (s, 2H), 6.51 (m, 2H), 7.33-7.43 (m, 5H), 7.64 (d, J=8.3 Hz, 1H), 12.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].Cl.Cl.[CH3:21][N:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1.N12CCCN=C1CCCCC2>C(#N)C>[ClH:1].[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([CH:23]3[N:22]([CH3:21])[CH2:28][CH:27]4[NH:29][CH:24]3[CH2:25][CH2:26]4)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CN1CC2CCC(C1)N2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C3C4CCC(CN3C)N4)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 0.54 g (2.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.50 g (2.5 mmol) of 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride [P. A. Sturm, et al, J. Med. Chem., 17, 481 (1974)], 0.75 ml (5.0 ml) 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile was heated under reflux for 1.5 hours and stirred overnight at room temperature. The reaction mixture was filtered and the solid washed with ethanol to give 0.46 g of the title compound, mp>310°.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)([CH2:20][CH3:21])[C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)([CH2:20][CH3:21])[C:17]([OH:19])([CH3:18])[CH2:2][C:1]#[N:3])=[CH:12][CH:11]=1
Reactant: CCC(C(C)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cccc21)C(C)(O)CC#N
Reaction time: 0.5 h

Procedure:
To a solution of acetonitrile (244 mg, 5.94 mmol) in THF (20 mL) was added n-BuLi (2.6 mL, 6.5 mmol, 2.5 M in hexane) dropwise at −78° C. After stirring for 0.5 h, a solution of the product from Step A (480 mg, 1.19 mmol) in THF (5 mL) was added to the mixture at −78° C. The resulting mixture was stirred at −78° C. for 0.5 h, and then quenched with saturated ammonium chloride solution, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (15/1 to 4/1, v/v) to afford the title compound as a colorless amorphous solid. LC/MS m/z=468.0 [M+Na]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:24])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29]>O.CCOC(C)=O>[Cl:33][C:32]([Cl:35])([Cl:34])[CH2:31][O:30][C:28](=[O:29])[NH:24][C:7]1[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cn(CCOC3CCCCO3)cn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cn(CCOC3CCCCO3)cn2)n1
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
To a mixture of Intermediate 119b (550 mg) in water (3 mL) and EtOAc (6 mL) was added NaOH (132 mg, 3.30 mmol). After 10 min stirring, 2,2,2-trichloroethyl chloroformate (273 μL, 1.98 mmol) was added and the reaction mixture was stirred at RT for 2 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-80% EtOAc in cyclohexane, to afford the title compound (175 mg). LCMS (Method 4): Rt 4.54 min, m/z 508, 510 [MH+].
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(O)=O>CCOC(C)=O.[Pt](=O)=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([NH:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2ncccc21
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2NCCCC21
Reaction time: 24 h

Procedure:
The product of Step 3 (2.66 g, 12.2 mmol) was added to a Parr shaker pressure vessel that was subsequently purged with nitrogen. Platinum (IV) oxide (0.277 g, 1.22 mmol) was added, followed by AcOH (27 mL). The vessel was placed on a Parr shaker apparatus and was sealed and evacuated and refilled with nitrogen 4 times (with shaking in between cycles). The vessel was then evacuated and refilled with hydrogen 4 times (with shaking in between cycles). The reaction was shaken under hydrogen pressure (approximately 60 psi; the vessel was recharged up to 60 psi as needed) for 48 hours. An additional amount of platinum (IV) oxide (0.277 g, 1.22 mmol) was added in order to drive the reaction to completion. After 24 hours, the reaction mixture was diluted with EtOAc (50 mL) and filtered through a Celite cartridge (Celite 545 Isolute®SPE column; Biotage, Inc.), rinsing the filter cake with additional EtOAc. The filtrate was concentrated in vacuo to a crude oil which was azeotroped with heptane several times until a constant weight was achieved, affording the desired product (HOAc salt). LRMS calc'd for C12H23N2O2 [M+H]+, 227; found 227.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:13])([F:12])[C:5]1[N:6]=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:10]1[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=1[C:4]([F:3])([F:12])[F:13]
Reactant: BrBr
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cnc(C(F)(F)F)c1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Bromine (4.62 g) was added in one portion to a stirred solution of 4-trifluoromethylpyrimidin-6-one (4.3 g) and sodium acetate (10.53 g) in acetic acid (43 ml). After stirring for 2 hours, the reaction mixture was left to stand for a period of 3 days, after which time it was heated to 80° C. for 1 hour. After cooling to the ambient temperature (ca 22° C.), the solvent was evaporated under reduced pressure. The resultant orange solid was dissolved in ethyl acetate, and washed several times with water. The combined agueous washings were extracted with ethylacetate, and the combined organic layers were washed with agueous sodium thiosulphate solution, followed by agueous sodium bicarbonate solution and brine. After drying over magnesium sulphate, evaporation of the solvent under reduced pressure gave 5-bromo-4-trifluoromethylpyrimidin-6-one as a white solid (4.8 g, mpt 226°-227° C.);
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:36](=[O:37])[C@H:32]([CH:33]([CH3:34])[CH3:35])[NH:31][C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (1.0 g, 4.2 mmol) in CH2Cl2 (21 mL) was treated with Et3N (0.76 mL, 5.44 mmol), dl-N-(tert-butoxycarbonyl)valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH2Cl2 (20 mL), and washed with 2 N NaOH solution (2×20 mL), brine (1×20 mL) and dried (MgSO4). Concentration and chromatography (SiO2, 3% CH3OH/CH2Cl2) afforded 1-(4-chlorobenzyl)-4-[{(N-Boc-valyl)amino}methyl]piperidine (1.1 g, 60%) as a pale amber oil: ESI/MS m/e 438 (M++H).