Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=O)[CH2:2][C:3]([O:5]C)=O.[CH3:10][O-].[Na+].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:19][C:13]1[CH:18]=[CH:17][C:16]([CH:1]=[CH:2][C:3](=[O:5])[CH3:10])=[CH:15][CH:14]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)CC(=O)OC
Reactant: C[O-]
Agent: [Na+]
Product: CC(=O)C=Cc1ccc(C)cc1

Procedure:
132 g of dimethyl malonate are introduced into 1 liter of toluene and 180 g of 30% strength sodium methylate solution are added at room temperature. A crystal slurry results, to which 160 g of p-methylbenzalacetone are added dropwise, with vigorous stirring. In the course of 3 hours, the reaction mixture is heated, with methanol distilling off azeotropically, until the temperature at which the vapors pass over has reached 110° C. 106 g of butyryl chloride are then added at 80°-90° C. and stirring is continued briefly. 5 g of 4-N,N-dimethylaminopyridine are added, the mixture is stirred for 3-4 hours at 100° C. and the solvent is then evaporated. A solution of 120 g of sodium hydroxide in 1.5 liters of water is added to the residue and the mixture is stirred for 2 hours at 80° C. It is then acidified with 270 ml of concentrated hydrochloric acid at 60° C., and when the mixture has cooled to room temperature the precipitate is filtered off with suction and washed neutral with water. After it has been dried, 239 g (88%) of 2-butyryl-5-(p-toluyl)-cyclohexane-1,3-dione, of melting point 76°-78° C., are obtained.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>[N+](CC)(CC)(CC)CC.[Cl-].C(#N)C>[Cl:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: CCCCCC(=O)OCc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CCCCCC(=O)OCc1cc(Cl)ncn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 915 mg (4.08 mMol) hexanoic acid 6-hydroxy-pyrimidin-4-ylmethyl ester, 1.48 g (8.98 mMol) Et4NCl and 698 μl (5.44 mMol) N,N-dimethylaniline in 30 ml of acetonitrile, 3.73 ml (40.8 mMol) POCl3 are added. After stirring for 1 h at 60° C., the cooled solution is concentrated in vacuo. The residue is re-dissolved in EtOAc and water, the aq. layer separated off and extracted twice with EtOAc. The organic phases are washed with water, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated, yielding the title compound as an oil: MS: [M+1]+=243/245; TLC(CH2Cl2): Rf=0.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.[CH2:19]=[C:20]([CH3:22])[CH3:21].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]2[CH2:19][C:20]([CH3:22])([CH3:21])[C:6]3[C:5](=[C:4]([CH3:9])[CH:3]=[C:2]([F:1])[CH:7]=3)[NH:8]2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(F)ccc1N
Reactant: O=Cc1cccc(Br)c1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
To a stirred solution of 4-fluoro-2-methyl-phenylamine (8.0 g, 64.0 mmol) and 3-bromobenzaldehyde (7.5 mL, 64.0 mmol) in acetonitrile (150 mL) were added isobutene (18.7 mL, 256.7 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.7 g, 7.7 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline (8.8 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 348.0 & 350.0.
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:13]>CN(C=O)C>[CH3:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[S:2][CH3:1])[C:9]#[N:10]
Reactant: Cc1cc(C#N)ccc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C#N)cc1C
Temperature: 80 °C

Procedure:
Sodium methanethiolate (1.60 g, 22.8 mmol) is added to a solution of 4-fluoro-3-methyl-benzonitrile (2.50 g, 18.5 mmol) in DMF, and the mixture is heated at 80° C. for 15 min. All volatiles are evaporated, and the residue is treated with water. The mixture is extracted with ethyl acetate twice, and the organic layer is dried over Na2SO4 and concentrated. Yield: 3.0 g (99% of theory); ESI mass spectrum: [M+H]+=164; r.t. HPLC: 0.61 min (X011_S03).
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][O:13][C:14](=[O:47])/[C:15](/[N:20]1[CH:23]([S:24]S(C2C=CC(C)=CC=2)(=O)=O)[CH:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21]1=[O:46])=[C:16](/[O:18][CH3:19])\[CH3:17]>O1CCCC1.C(Cl)Cl>[CH3:12][O:13][C:14]([C@@H:15]1[N:20]2[C:21](=[O:46])[C@@H:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:23]2[S:24][CH:17]=[C:16]1[O:18][CH3:19])=[O:47]
Reactant: COC(=O)/C(=C(\C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C(OC)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12

Procedure:
302 mg (2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to a solution of 534 mg (1 mmol) of a mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid methyl ester and 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoacetidin-1-yl]-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1, in 20 ml of tetrahydrofurane, whilst stirring. The mixture is then stirred for 40 minutes, diluted with 70 ml of methylene chloride and washed successively with dilute hydrochloric acid, with water, with dilute aqueous sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 15 g of acid-washed silica gel using toluene/ethyl acetate, 2:1 followed by 1:1, resulting in the elution of, first, pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90 and 8.25μ, followed by pure 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90 and 7.10μ, in the form of colourless foams.
Reaction SMILES: [ClH:1].Cl.Cl.[O:4]([C:11]1[C:12]([NH:27][C:28]2[S:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:29]=2)=[N:13][CH:14]=[C:15]([S:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[CH:25][S:26][C:19]=23)[CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[ClH:1].[ClH:1].[O:4]([C:11]1[C:12]([NH:27][C:28]2[S:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:46](=[O:48])[CH3:47])[CH2:35][CH2:34]3)[N:29]=2)=[N:13][CH:14]=[C:15]([S:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[CH:25][S:26][C:19]=23)[CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 147.2 %

Procedure:
A 250 mL flask was charged with 3-phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (5.6 g, 8.92 mmol), triethylamine (9.94 mL, 71.3 mmol), and CH2Cl2 (100 mL). Acetic anhydride (1.26 mL, 13.4 mmol) was added and the reaction was stirred at ambient temperature for 10 minutes. The reaction was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica (5 to 10% methanol in EtOAc) to afford 1-(4-(5-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone dihydrochloride (4.16 g, 73.6% yield) as a yellow solid after HCl salt formation. 1H NMR (d6-DMSO) δ 12.48 (bs, 1H), 8.56 (d, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.40 (m, 2H), 7.18 (m, 1H), 7.14 (m, 2H), 7.07 (d, 1H), 4.32 (m, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.77 (m, 1H), 2.01 (m, 5H), 1.73 (m, 1H), 1.59 (m, 1H). Mass spectrum (apci) m/z=561.3 (M+H-2HCl).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6](N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[C:29]([C:31]2[C:32]([CH3:36])=[N:33][O:34][CH:35]=2)[CH:28]=[C:27]([CH3:37])[N:26]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:27]1[N:26]=[C:25]([NH:24][C:4]2[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:30]=[C:29]([C:31]2[C:32]([CH3:36])=[N:33][O:34][CH:35]=2)[CH:28]=1
Reactant: Cc1cc(-c2conc2C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2conc2C)cc(Nc2cccnc2C#N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate (50 mg, 0.099 mmol) in DCM (1 ml) was added TFA (1.0 ml, 13 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 54(1R,2S)-2-aminocyclohexylamino)-3-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)picolinonitrile. MS ESI calc'd. for C22H26N7O [M+H]+ 404. found 404.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[Cl:41])(=[O:50])=[O:49])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CN(CCc1c(CCNS(=O)(=O)c2ccccc2Cl)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12)c1ccc(C(=O)O)cc1
Yield: 96 %

Procedure:
The intermediate from example 146 step 7 was treated with 2-chlorobenzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 96% yield.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][C@H:22]([C@@H:25]1[CH2:29][C@@H:28]([CH3:30])[CH:27](OC(=O)C)[O:26]1)[CH2:23][CH3:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][C@H:22]([C@@H:25]1[CH2:29][C@@H:28]([CH3:30])[C@H:27]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:26]1)[CH2:23][CH3:24])(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:13]([O:21][C@@H:22]([C@@H:25]1[CH2:29][C@@H:28]([CH3:30])[C@H:27]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:26]1)[CH2:23][CH3:24])(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(OC(C)=O)O1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC[C@@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Product: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (872 mg, 4.7 mmol) in ACN (20 mL) was added BSA (913.5 mg, 4.5 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 2 hours to form a clear solution. After the solution was cooled to room temperature, [(1S)-1-[(2S,4R)-5-acetoxy-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28j, 294 mg, 0.95 mmol) and TMSOTf (1.44 g, 6.6 mmol) were added in sequence. After being stirred with stirring at 20° C. for 14 hrs, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified and separated by preparative HPLC to afford 9.7 mg of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28k-A) and 8.4 mg of [(1R)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28k-B) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([C:17]([O:19][CH3:20])=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14].C(O)C>CO>[CH3:16][O:15][C:13](=[O:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:2]=1[Br:1])=[CH:11][C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(N)c(Br)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Solvent: CCO
Product: COC(=O)C=C(Nc1ccc(OC)cc1Br)C(=O)OC
Yield: 93 %

Procedure:
A solution of 2-bromo-4-methoxy aniline (6.02 g, 29.8 mmol) in 125 mL anhydrous methanol was treated with dimethyl acetylenedicarboxylate (3.70 mL, 30.2 mmol) and the solution was heated at reflux under nitrogen for 8 hours. The reaction mixture was cooled, concentrated, and redissolved in hot methanol. Yellow crystals were obtained by filtration (6.93 g, 68%). A second crop of crystals was obtained from ethanol (0.942 g, 9%). The filtrates were combined and purified by flash chromatography on silica gel using 4:1 hexanes:ethyl acetate to afford an additional 1.63 g (16%) for a total yield of 93%. 1H NMR (300 MHz, DMSO, d6) δ 9.60 (s, 1 H, NH), 7.26 (d, 1 H, Jm=2.7 Hz, ArH3), 6.93 (dd, 1 H, Jo=8.7, Jm=2.7 Hz, ArH5), 6.87 (d, 1 H, Jo=8.7 Hz, ArH6), 5.34 (s, 1 H, C═CH), 3.76 (s, 3 H, OCH3), 3.68 (s, 3 H, CHCO2CH3), 3.66 (s, 3 H, CNCO2CH3); Mass Spec.: calc. for [C13H14BrNO5+H]+ Theor. m/z=344, 346; Obs. 344, 346.
Reaction SMILES: [Na].[O-]CC.[Na+].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:17]([CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Yield: 85 %

Procedure:
200 ml of ethanol was put in a 1-liter four-necked flask, 7.6 g of metal sodium cut into pieces was put therein portionwise to prepare sodium ethoxide. To this were added dropwise 54.6 g of diethyl malonate and then 63.9 g of octyl bromide. Thereafter, the mixture was refluxed for 3 hours. Then, the most part of ethanol was distilled away under the atmospheric pressure, 200 ml of water was added, and the mixture was extracted with 250 ml of ether. The ether solution was dried over sodium sulfate, ether was distilled away, and the residue was distilled under reduced pressure to give 72.1 g of a colorless oily substance (b.p. 111° C./2 mmHg). Yield 85%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[C:12]([CH3:13])[C:5]=2[O:4]1.C1COCC1.[C:22]1([C@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC>O.CCOCC>[C:22]1([CH:32]([NH:34][C:14]([C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][CH:3]([CH2:2][OH:1])[O:4][C:5]=3[C:12]=2[CH3:13])=[O:16])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(C(=O)O)ccc2c1OC(CO)CO2
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)NC(C)c2cccc3ccccc23)ccc2c1OC(CO)CO2

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid (2.00 g, 8.92 mmol), THF (45 mL), (R)-(+)-1-(1-naphthyl)ethylamine (2.23 mL, 8.92 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.53 g, 9.81 mmol). This mixture was stirred at room temperature for 36 hours. A few drops of water were added and the mixture stirred for 5 minutes. The reaction was diluted with ether and washed once with 1N HCl, once with saturated sodium bicarbonate(aq), once again with 1N HCl, dried over magnesium sulfate, filtered and evaporated to provide 3-hydroxymethyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (1-naphthalen-1-yl-ethyl)-amide. Crystals of acceptable purity for x-ray crystallography were obtained by subliming the material twice under vacuum at 60° C. This x-ray analysis established the regiochemistry and the absolute stereochemistry of the compounds as shown, since the configuration of the naphthylethylamine stereocenter is known and not subject to racemization under the conditions of synthesis. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 1.71 (d, 3H), 2.22 (s, 3H), 3.80 (m, 2H), 4.06 (m, 1H), 4.23 (m, 2H), 4.32 (m, 1H), 6.09 (m, 1H), 6.65 (d, 1H), 6.87 (d, 1H), 7.55 (m, 3H), 7.69 (m, 2H), 7.83 (d, 1H), 7.94 (d, 1H), 8.35 (d, 1H); TLC Rf=0.12 (1:1 ethyl acetate/hexane).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>>[O:8]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1CCCCC1Cl
Product: O=C1CCCCC1N1C(=O)c2ccccc2C1=O

Procedure:
The amine required as precursor was prepared in accordance with GB1131191. 2-Chlorocyclohexanone was reacted with phthalimide to give 2-(2-oxocyclohexyl)isoindole-1,3-dione, which was ketalized with ethylene glycol in the presence of para-toluenesulfonic acid, giving 2-(1,4-dioxaspiro[4.5]dec-6-yl)isoindole-1,3-dione. Treatment with hydrazine hydrate to remove the phthalimideradical gave the desired 1,4-dioxaspiro[4.5]dec-6-ylamine.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([CH:10]=O)[CH:8]=O)[N:4]=[CH:3][CH:2]=1.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH:20][NH2:21])[CH:17]=[CH:18][CH:19]=1>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([N:20]2[CH:10]=[C:7]([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=3)[CH:8]=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=CC(C=O)c1ccccn1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: Brc1cccc(-n2cc(-c3ccccn3)cn2)c1
Temperature: 75 °C

Procedure:
2-(2-Pyridyl)malondialdehyde (100 mg, 0.67 mmol) and 3-bromophenylhydrazine hydrochloride (150 mg, 0.67 mmol) were suspended in ethanol (2 mL), and heated to 75° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel preparative TLC eluting with hexanes:EtOAc (3:1) to afford 2-[1-(3-bromophenyl)-1H-pyrazol-4-yl]pyridine as a pale yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 8.61 (d, J=4.8 Hz, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.73-7.68 (m, 2H), 7.55 (d, J=7.9 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.17 (dd, J=4.9, 7.4 Hz, 1H). MS (ESI) 300.0, 302.0 (M++H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:15][C:14]([CH3:17])([CH3:16])[C@H:13]([OH:18])[CH2:12]2)=[N:4][C:5]([CH3:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:39]=[O:40])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:9][NH:8][C:7]2[C:2]([F:1])=[C:3]([N:11]3[CH2:12][C@@H:13]([OH:18])[C:14]([CH3:16])([CH3:17])[CH2:15]3)[N:4]=[C:5]([CH3:10])[N:6]=2)=[O:27])[CH2:29][N:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[O:40])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2C[C@@H](O)C(C)(C)C2)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2C[C@@H](O)C(C)(C)C2)n1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (3S)-1-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-4,4-dimethyl-3-pyrrolidinol (0.125 g, 0.490 mmol) in DMF (3 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.1246 g, 0.408 mmol), N-methylmorpholine (0.225 ml, 2.046 mmol), 1-hydroxy-7-azabenzotriazole (67 mg, 0.492 mmol), and EDC (94 mg, 0.490 mmol). The mixture was stirred overnight and then purified directly by Gilson RPLC to give [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1606 g, 73% yield) as a purple oil. LCMS: (M+H)+: 543.3.
Reaction SMILES: B#B.[CH2:3]([N:5]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:4].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(OCC)(=O)C>[C:27]([O-:32])(=[O:31])[C:28]([O-:30])=[O:29].[CH2:3]([NH+:5]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:4].[CH2:3]([NH+:5]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:4]
Reactant: CCCCCCCCN(CC)CCCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C(=O)O
Agent: B#B
Solvent: CCOC(C)=O
Product: CCCCCCCC[NH+](CC)CCCCc1ccc([N+](=O)[O-])cc1
Product: O=C([O-])C(=O)[O-]

Procedure:
Reduction of the acylated amine was effected by reaction with diborane according to the procedure of Example 1. The reduced amine, N-ethyl-N-n-octyl-4-(4-nitrophenyl)butylamine, was converted to the oxalate salt by reaction with oxalic acid in ethyl acetate. After several recrystallizations from isopropanol there was recovered 3.9 g. of N-ethyl-N-n-octyl-4-(4-nitrophenyl)butylaminium oxalate. M.P. 105°-108° C.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[S:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[CH:13][C:12]([C:24]#[N:25])=[N:11]2)=[CH:6][CH:5]=1)=O.[H-].[Na+].I[CH3:29].Cl.CN(C)[CH:33]=[O:34]>>[CH:33]([CH2:29][NH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[S:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[CH:13][C:12]([C:24]#[N:25])=[N:11]2)=[CH:6][CH:5]=1)=[O:34]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(NC=O)cc2)s1
Reactant: CN(C)C=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(NCC=O)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[4-(formylamino)phenyl]-5-[5-(methylsulfonyl)-2-thienyl]pyrazole-3-carbonitrile (1.1 g) in N,N-dimethylformamide (3 ml) was added dropwise to a suspension of sodium hydride (60%; 118 mg) in N,N-dimethylformamide (2 ml). The mixture was stirred at 0° C. for 30 minutes. To the mixture was added dropwise a solution of iodomethane (0.84 g) in N,N-dimethylformamide (2 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, poured into an ice-cooled dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 1-[4-(N-formylmethylamino)phenyl]-5-[5-(methylsulfonyl)-2-thienyl]pyrazole -3-carbonitrile (1 g).