Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[P:17](=[S:25])(Cl)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CN(C)C=O>[P:17](=[S:25])([O:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[C:5]([F:9])[N:4]=1)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]
Reactant: Oc1nc(F)c(Cl)cc1Cl
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=S)(OCC)Oc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture was prepared by admixing, with stirring, 9.7 g (0.053 m) of 3,5-dichloro-6-fluoro-2-pyridinol, 5.6 g (0.053 m) of sodium carbonate and 100 ml of dimethylformamide. To this mixture was added all at once, at room temperature, with stirring, 9.9 g (0.053 m) of O,O-diethyl phosphorochloridothioate. The resulting mixture was heated at 60°-65° C. with stirring for one hour. The mixture was cooled to room temperature and filtered to remove insolubles. The solvent was removed by distillation under reduced pressure and the residue dissolved in 100 ml of benzene. The mixture was washed with water and the organic layer separated, dried and filtered. The benzene was removed by evaporation under reduced pressure. The residue (15 g) was crystallized from 15 ml of hexane giving 5.9 g of the desired O,O-diethyl O-(3,5-dichloro-6-fluoro-2-pyridinyl) phosphorothioate. The product melted at 31°-33° C. and upon analysis, was found to have carbon, hydrogen and nitrogen contents of 32.30, 3.30 and 4.19 percent, respectively, as compared with the theoretical contents of 32.36, 3.32 and 4.19 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(O)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Yield: 56.6 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (230 mg, 0.806 mmol) was dissolved in ethyl acetate (5 mL). Degussa wet (50 wt % water) 10% Pd/C (223 mg, 0.105 mmol) was added and the mixture was stirred in a hydrogenation reactor under 95 psi hydrogen for 3 h. The mixture was filtered through Celite®. The filtrate was concentrated and purified by silica gel flash chromatography to provide the title compound as a white solid (131 mg). LCMS m/z=288.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=1
Reactant: Cc1cc(F)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95.1 %

Procedure:
2-Fluoro-4-methyl-5-nitropyridine (0.8 g, 5.12 mmol), tert-butyl piperazine-1-carboxylate (1.05 g, 5.64 mmol) and potassium carbonate (0.85 g, 6.15 mmol) were taken up in acetonitrile (15 mL) and heated at 60° C. for 1.5 h. After this time, the reaction was quenched with water (20 mL) and extracted with EtOAc (2×30 mL). The organic layers were combined and dried over sodium sulphate, then concentrated in vacuo. The crude material was purified by column chromatography (silica gel: 100-200 mesh, 1:1 EtOAc/heptane) to give the title compound (1.57 g, 97%). LCMS (ES+) 323.1 (M+H)+, RT 1.71 minutes (method 4).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])C.[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH2:4]([OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO

Procedure:
The acid chloride of 1-triacontanoic acid is converted to the ester by adding methanol or ethanol and stirring for 1/2 to 1 hour. The alcohol was evaporated on a rotary evaporator leaving ethyl-1-triacontanoate. The ester is then reacted in a pressure vessel under about 250 atmospheres of hydrogen in the presence of a powdered copper chromite catalyst for about 12 hours at 250° C. to produce 1-triacontanol. One part of catalyst is present for every 5 to 10 parts of ester.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12]Cl)[CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)[CH:2]=[CH2:3].CCCCCC.C([Li])CCC.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:4]1[CH2:11][CH2:12][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN(CCCl)Cc1ccoc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCN1CCc2occc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 9.03 g of the above crude N-allyl-N-(3-furylmethyl)-2-chloroethylamine in 200 ml of tetrahydrofuran, 63.8 ml (102 mmol) of 1.6 M n-butyl lithium hexane was added under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield 5-allyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4]([O:6][C:7](OCC)=[CH:8][C:9]([O:11]CC)=O)[CH3:5].O.S(=O)(=O)(O)O>C(O)C.[Cl-].[Na+].O>[CH2:4]([O:6][C:7]1[CH2:8][C:9](=[O:11])[N:2]([CH3:1])[N:3]=1)[CH3:5]
Reactant: CCOC(=O)C=C(OCC)OCC
Reactant: CNN
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC1=NN(C)C(=O)C1
Yield: 42.5 %

Procedure:
Methylhydrazine (2.6 g, 0.056 mole) was added to a solution of ethyl 3,3-diethoxyacrylate (10.0 g, 0.053 mole) in ethanol (50 mL) and the mixture was heated and held at reflux for 18 hours. After cooling, water, saturated brine, and 3 mL of concentrated sulfuric acid were added; and the product was extracted with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using ethyl acetate/cyclohexane gave 5-ethoxy-2,4-dihydro-2-methyl-3H-pyrazol-3-one (3.2 g, 42% yield) as a white solid, mp=79°-80° C.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6](Cl)=[O:7])[CH3:2].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1.O>N1C=CC=CC=1>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:6](=[O:7])/[CH:5]=[CH:4]/[O:3][CH2:1][CH3:2])=[C:12]([CH3:17])[CH:11]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCO/C=C/C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCO/C=C/C(=O)Nc1ccc(Br)cc1C

Procedure:
Trans-3-ethoxypropenoyl chloride (0.74 g) was added at 0° to a stirred solution of 4-bromo-2-methylaniline (0.93 g) in pyridine (10 cm3). After 0.5 hours water (40 cm3) was added, the solid material was filtered off, washed with water (30 cm3) and dried. The product was recrystallised from ethyl acetate to afford trans-N-(4-bromo-2-methylphenyl)-3-ethoxypropenamide, m.p. 163°-164°, (1.3 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:22][C:23](=O)[C:24](=O)[CH3:25]>C(O)C>[CH3:22][C:23]1[C:24]([CH3:25])=[N:21][C:16]2[C:17](=[CH:18][CH:19]=[C:14]([S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)(=[O:13])=[O:12])[CH:15]=2)[N:20]=1
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1N
Reactant: CC(=O)C(C)=O
Solvent: CCO
Product: Cc1nc2ccc(S(=O)(=O)c3cccc4cnccc34)cc2nc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a mixture of 4-(5-isoquinolylsulfonyl)benzenediamine 500 mg (1.7 mmol) and ethanol 10 ml, 2,3-butanedione 1.2 ml was added, and the mixture was heated with stirring for 2 hours at 90° C. The reaction mixture was concentrated under reduced pressure, and ether was added to the resulting residue to crystallize. The crystals were filtered, and 2,3-dimethyl-6-(5-isoquinolylsulfonyl)quinoxaline 490 mg (84.7%) was obtained.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[Br:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]([NH2:12])[CH3:1])[CH:6]=1
Reactant: C[Mg]Br
Reactant: N#Cc1cc(Br)ccn1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methylmagnesium bromide (3 M in THF) (63.4 mL, 190 mmol) in THF (100 mL) A solution of 4-bromopyridine-2-carbonitrile (11.6 g, 63.4 mmol; patent US 2009/0239876 A1, example 2) in THF (40 mL) was added drop-wise at room temperature over 40 min. Methanol (40 mL) was then added drop-wise followed by portion-wise addition of sodium borohydride (11.8 g, 312 mmol) in several batches. The resulting mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate (200 mL). The pH of the mixture was adjusted to 9 with aqueous sodium hydroxide (1 M) and the solids were removed by filtration. The filtrate was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 10.3 g (crude) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([C:19](=[O:20])[NH:27][CH3:26])[CH:22]=[CH:23][C:24]=3[CH3:25])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Product: CNC(=O)c1ccc(C)c(NC(=O)c2ccc(-c3ccc(Cl)cc3)s2)c1
Yield: 73 %

Procedure:
The title compound (Example 186) was prepared by reacting 3-(5-(4-chlorophenyl)thiophene-2-carboxamido)-4-methylbenzoic acid C with methylamine using the method described in Example 128 to afford a white solid in 73% yield. HPLC Ret. Time=3.51 min, LCMS [M+H]+ 385.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([NH2:26])=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C(N)=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C#N)c12
Yield: 67.1 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (850 mg 2.07 mmol) in N,N-dimethylformamide (10 mL) was added thionyl chloride (0.448 mL, 6.21 mmol). The resultant mixture was stirred at 50° C. for 30 min and poured into saturated aqueous sodium hydrogen carbonate at 0° C. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether to give the title compound as a colorless solid (532 mg, 1.39 mmol, 67%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[H-].[Na+]>O1CCOCC1>[Br:7][C:8]1[CH:9]=[N:10][C:11]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:12][CH:13]=1
Reactant: OC1CCCC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1cnc(OC2CCCC2)nc1
Temperature: 0 °C

Procedure:
36.3 μL (0.40 mmol) cyclopentanol and 38.7 mg (0.20 mmol) 5-bromo-2-chloro-pyrimidine are added to 1.5 mL dioxane and cooled down to 0° C. Then the reaction mixture is charged with 24.0 mg NaH. After removing of the cooling bath the reaction mixture is stirred at r.t. over night. The reaction is quenched by the addition of water. The solvent is removed under vacuo and the residue is dissolved in DCM, washed with water and dried with MgSO4. The solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: [O-]CC.[Na+].CO[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1OC)[CH2:10][C:11]#N.C(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:9]1([CH:10]=[CH:11][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][CH:15]=[CH:7][CH:8]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C(=Cc1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
In a round-bottom flask, 380 mg (5.64 mmol, 0.1 eq.) of sodium ethoxide was added to a suspension of 10.0 g (56.43 mmol) of 3,4-dimethoxybenzyl cyanide and 5.99 g (56.43 mmol, 1.0 eq.) of benzaldehyde in 150 mL of ethanol under an argon atmosphere at room temperature while stirring, and the resulting mixture was heated to reflux (the oil bath temperature: 85° C.). After three hours, the disappearance of the raw materials was confirmed, and the resulting reaction liquid was cooled on ice to precipitate a solid. The solid was then collected by suction filtration using a Büchner funnel and a filtering flask, which was then washed with 100 mL of methanol twice. The solid was dried under reduced pressure at 60° C. to give 13.70 g (92%) of light yellow powder.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[O:6]=[C:7]1[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=[C:9]([C:16]([F:19])([F:18])[F:17])[NH:8]1.[ClH:20]>ClCCCl.N1C=CC=CC=1>[Cl:20][C:10]1[CH:11]=[C:12]([C:13]([NH2:15])=[O:14])[C:7](=[O:6])[NH:8][C:9]=1[C:16]([F:17])([F:19])[F:18]
Reactant: NC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Reactant: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: NC(=O)c1cc(Cl)c(C(F)(F)F)[nH]c1=O

Procedure:
At room temperature, 0.39 g (2.9 mmol) of sulfuryl chloride was added to 300 mg (1.46 mmol) of 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide in 5 ml of 1,2-dichloroethane and 2.3 g (0.25 ml) of pyridine, and the mixture was then heated under reflux for 2 h. The mixture was then added to 0.5N hydrochloric acid. The organic phase was removed and then dried and concentrated, which gave 144 mg (41% of theory) of a brownish powder.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:25]([O-])([O-:27])=[O:26].[NH4+]>C(Cl)Cl>[N+:25]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:11])=[CH:6][CH:7]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCCc2ccccc21
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 41.2 %

Procedure:
14.62 g of 1-tetralone in 45 ml of methylene chloride were treated with 29.3 ml of trifluoroacetic anhydride and 8.40 g of ammonium nitrate while cooling with ice/NaCl. After 18 hours the mixture was poured cautiously into an ice/conc. NaOH solution and extracted with diethyl ether. The organic phase was washed in succession with soda solution and NaCl solution, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate=9/2) followed by recrystallization from hexane/ethyl acetate (1/1) yielded 7.87 g of 7-nitro-1-tetralone as brownish crystals of m.p. 104°-105° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][NH2:26]>>[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCC1CCCO1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC3CCCO3)s2)c(C)[nH]c1=O
Yield: 39.5 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (tetrahydrofuran-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a yellow solid (39.5% yield). LC/MS: RT 2.63 min; m/e 383 (M+H); 1H NMR (CDCl3, δ, ppm): 11.21 (H, br), 7.50 (1H, d), 7.23 (1H, s), 6.90 (1H, d), 4.98 (1H, t), 4.00 (1H, q), 3.80 (2H, m), 3.30 (1H, m), 3.05 (1H, m), 2.6 (2H, dd), 2.40 (3H, s), 1.87 (3H, m), 1.23 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23](=[O:36])[CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]([CH3:27])[CH3:26])[CH:17]=[CH:16][N:15]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:44][CH:45]([Cl:49])[C:46](Cl)=[O:47]>C(Cl)Cl>[Cl:44][CH:45]([Cl:49])[C:46]([N:20]([CH2:21][CH2:22][C:23](=[O:36])[CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]([CH3:27])[CH3:26])[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH:13]=2)[CH:19]=1)=[O:47]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
tert-Butyl 6-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)-2-methyl-4-oxohexan-3-ylcarbamate (445 mg, 0.83 mmol) was dissolved in methylene chloride (10 mL) with triethylamine (140 μL, 1.0 mmol). The solution was cooled on an ice-water bath and then a solution of dichloroacetyl chloride (100 μL, 1.0 mmol) in methylene chloride (1 mL) was added dropwise. The reaction mixture was allowed to stir overnight while warming to room temperature. The solution was washed successively with water and saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 0.5:99.5 methanol:methylene chloride to provide tert-butyl 6-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-2-methyl-4-oxohexan-3-ylcarbamate (185 mg) as a pink foam. 1H NMR (CDCl3): 8.85 (d, 1H), 7.91 (d, 1H), 7.61-7.35 (m, 5H), 7.18 (s, 1H), 6.11 (s, 1H), 5.02 (d, 1H), 4.28-4.08 (m, 2H), 3.15-2.82 (m, 3H), 2.20-2.10 (m, 1H), 1.42 (s, 9H), 1.08 (d, 3H), 0.85 ppm (d, 3H). MW=644 confirmed by LC-MS, tr=16.72 min (Method Y) MH+=642-646.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH3:8][C:9]([CH3:11])=O.[OH-].[Na+]>CO.[Pd]>[ClH:1].[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][CH:9]([CH3:11])[CH3:8]
Reactant: CC(C)=O
Reactant: COC(=O)CN
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CNC(C)C
Yield: 19.6 %

Procedure:
Part A: A mixture of glycine methyl ester hydrochloride (3.83 g, 30.5 mmol), acetone (1.77 g, 30.5 mmol) and NaOH (1.22 g, 30.5 mmol) in MeOH (200 mL) was stirred under an atmosphere of hydrogen (1 atm) in the presence of palladium on carbon (10%, 0.4 g) for 24 hours. The reaction was flushed with nitrogen and filtered through a Celite pad, acidified with HCl (1N), dried (MgSO4) and evaporated. Trituration of the residue with Et2O gave N-2-propylglycine methyl ester hydrochloride (1.0 g) as an off-white solid; LRMS (M+H)+ =132.1.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16](O)=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29]CC)=O)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.CN(C)C=O>[CH:1]1[C:14]2[C:13]3([CH2:16][N:23]4[CH2:24][CH2:25][CH:26]([CH:27]([C:25]5[CH:24]=[N:23][CH:33]=[CH:32][CH:26]=5)[OH:29])[CH2:32][CH2:33]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccccc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: OC(c1cccnc1)C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (21.8 g, 92.4 mmol) in toluene (160 mL) was treated with thionyl chloride (11.7 g, 99 mmol) and N,N-dimethylformamide (0.1 g). The resulting solution was heated to reflux temperature for 2 h, then was cooled to room temperature. The mixture was then treated dropwise with a solution of ethyl isonipecotate (31.1 g, 198 mmol) in toluene (20 mL), using an ice/water bath to keep the reaction temperature <35° C. Upon complete addition, the mixture was stirred for 1 h at room temperature, then was washed sequentially with 10% hydrochloric acid (40 mL), water (40 mL), 1N aqueous sodium hydroxide (40 mL), water (40 mL) and brine (40 mL). The aqueous washes were extracted with toluene (100 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated to afford the title compound (33.0 g, 85.2 mmol, 92%) as an off-white solid. 1H NMR (d6-DMSO): δ7.33-7.14 (m, 4H), 6.99 (m, 4H), 4.54 (br, 1H), 4.38 (s, 1H, H--C(10)), 4.09 (q, J=6.5 Hz, 2H, CH2CH3), 3.8 (br, 1H), 3.0-2.5 (br, 6H), 2.05-1.45 (br, 5H), 1.19 (t, J=6.5 Hz, 3H, CH2CH3).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][NH:16][CH2:17]C)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OP(OCCN(C)C(=O)OCC1C=CC=CC=1)(OC(C)(C)C)=O)(C)(C)C>>[P:1]([O:13][CH2:14][CH2:15][NH:16][CH3:17])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:2]
Reactant: CCNCCOP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CNCCOP(=O)(OC(C)(C)C)OC(C)(C)C
Yield: 95 %

Procedure:
A similar procedure to that described for INTERMEDIATE 49 utilizing benzyl 2-(di-tert-butoxyphosphoryloxy)ethyl(methyl)carbamate (INTERMEDIATE 52, 0.59 g, 1.47 mmol) as starting material was followed, to give the title product (370 mg, yield: 95%).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.CCOCC.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=1)=[O:34])[CH3:10]
Reactant: O=C(Cc1ccccn1)c1ccccn1
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)C(C(=O)c1ccccn1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 141.5 %

Procedure:
A solution of 15 mL (0.089 mol) of triethyl orthoformate in 100 mL of methylene chloride was stirred under nitrogen at -78° C. and 13.2 mL (0.108 mol) of boron trifluoride etherate was added. The solution was allowed to warm to 0° C., recooled to -78° C., and a solution of 8.0 g (0.04 mol) of 1.2-bis(2-pyridinyl)ethanone in 75 mL of methylene chloride was added, followed after 30 min by 22 mL (0.132 mol) of diisopropylethylamine in 30 mL of methylene chloride. The reaction was stirred 45 min at -78° C., poured into 400 mL of water containing 10 g of NaHCO3 and stirred 20 min. The phases were separated, the methylene chloride layer was dried over MgSO4 and stripped to yield about 17 g of crude 3,3-diethoxy-1,2-bis(2-pyridinyl)-1-propanone.