Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C2C=C3C(=CC=2)NC(=O)C3C(OCC)=O)OCCO1.CN1C2C(=CC(C3(C)OCCO3)=CC=2)C(C(OCC)=O)C1=O.[CH2:44]([N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3([CH3:61])[O:60][CH2:59][CH2:58][O:57]3)=[CH:53][CH:54]=2)[CH:49]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[C:48]1=[O:67])[CH2:45]C.C(N1C2C(=CC(C3(C)OCCO3)=CC=2)C(C(OCC)=O)C1=O)(C)C>>[CH2:44]([N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3([CH3:61])[O:60][CH2:59][CH2:58][O:57]3)=[CH:53][CH:54]=2)[CH:49]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[C:48]1=[O:67])[CH3:45]
Reactant: CCCN1C(=O)C(C(=O)OCC)c2cc(C3(C)OCCO3)ccc21
Agent: CCOC(=O)C1C(=O)N(C(C)C)c2ccc(C3(C)OCCO3)cc21
Agent: CCOC(=O)C1C(=O)N(C)c2ccc(C3(C)OCCO3)cc21
Agent: CCOC(=O)C1C(=O)Nc2ccc(C3(C)OCCO3)cc21
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C)OCCO3)cc21

Procedure:
ethyl 5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate, ethyl 1-methyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate, ethyl 1-n-propy-l-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and ethyl 1-i-propyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:51]1([CH2:54][C@H:55]([NH2:62])[C:56]2[N:60]=[C:59]([CH3:61])[O:58][N:57]=2)[CH2:53]C1>>[CH:54]1([CH:55]([NH:62][C:18]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:8]=2)=[O:20])[C:56]2[N:60]=[C:59]([CH3:61])[O:58][N:57]=2)[CH2:51][CH2:53]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: Cc1nc(N(C)C2CC2)no1
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: Cc1nc(C(NC(=O)c2ccc(C3CC3)c(OCC3CCOCC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e=413.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7].[Br:9][CH:10]([CH3:14])[C:11](Br)=[O:12]>>[Br:9][CH:10]([CH3:14])[C:11]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7])=[O:12]
Reactant: COC(=O)NCCO
Reactant: CC(Br)C(=O)Br
Product: COC(=O)NCCOC(=O)C(C)Br

Procedure:
by using methyl 2-hydroxyethylcarbamate and 2-bromopropionyl bromide there is obtained methyl 2-(2-bromopropionyloxy)-ethylcarbamate, nD20 1.4779;
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH2:9][O:8][C:7](=[O:10])[CH:6]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=1.CO>O1CCCC1>[Cl:21][C:19]1[CH:20]=[C:15]([CH2:14][N:4]([CH2:3][CH2:2][F:1])[C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)[CH:16]=[N:17][C:18]=1[Cl:22]
Reactant: O=C1C=C(NCCF)CO1
Reactant: Clc1cc(CBr)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C=C(N(CCF)Cc2cnc(Cl)c(Cl)c2)CO1
Temperature: 25 °C

Procedure:
217 mg (1.49 mmol) of 4-[(2-fluoroethyl)amino]furan-2(5H)-one (VI-1) and 90 mg (2.24 mmol) of a 60% strength dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 2 hours. After cooling to room temperature, 360 mg (1.49 mmol) of 3-(bromomethyl)-5,6-dichloropyridine are added, and the mixture is heated under reflux for a further 3 hours. After cooling to room temperature and addition of methanol, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. After concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (5:1), 260 mg (56% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](2-fluoroethyl)amino]furan-2(5H)-one are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:17][S:18][CH2:19][C@@H:20]([NH2:22])[CH3:21].CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:9]([C:10]#[CH:11])=[C:8]([NH:22][C@@H:20]([CH3:21])[CH2:19][S:18][CH3:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CSC[C@H](C)N
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C#Cc1c(N[C@@H](C)CSC)ccc(C#N)c1Cl

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.120 g, 0.477 mmol), (S)-1-(methylthio)propan-2-amine (0.075 g, 0.715 mmol) (prepared essentially as described in US2005182275A1) and DIEA (0.166 mL, 0.953 mmol) in DMSO (2 mL) was heated (sealed tube) at 100° C. for 45 min. Upon cooling, the reaction mixture was diluted with EtOAc (25 mL) and washed with water (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to give the intermediate (S)-2-chloro-3-ethynyl-4-((1-(methylthio)propan-2-yl)amino)benzonitrile. This intermediate was dissolved in NMP (2 mL), treated with KOtBu (1 M in THF) (1.430 mL, 1.430 mmol) and heated at 60° C. The reaction was monitored by LCMS, and after 45 min, additional KOtBu (1 M in THF) (1.430 mL, 1.430 mmol) was added and heating continued for another 1 h. Upon cooling, the reaction mixture was diluted with EtOAc (25 mL) and washed with water (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 5-30% EtOAc-hexane gradient to give (S)-4-chloro-1-(1-(methylthio)propan-2-yl)-1H-indole-5-carbonitrile (0.056 g, 42% yield): MS (ESI): m/z 265 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cc(Cl)ccc1Cl
Temperature: 80 °C
Yield: 83.6 %

Procedure:
A mixture of 2,5-dichlorobenzyl bromide (5.4 g, 22.5 mmol) in 16 mL of ethanol and potassium cyanide (1.63 g, 25 mmol) in 4 mL of water was heated at 80° C. overnight, then cooled, and the solids were filtered and washed with ethanol to give 3.5 g of 2,5-dichlorophenylacetonitrile as a white powder melting at 89-91° C. The nitrile was suspended in 20 red, of ethanol, and 20 mL of a 25% aqueous NaOH solution was added. The mixture was heated in a CEM Explore™ microwave reactor at 140° C. for 30 minutes, then cooled, poured into ice water and acidified to pH 1 with concentrated HCl to give a precipitate. The precipitate was filtered, washed with water and dried in a vacuum oven at 90° C. for 5 h to give the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[CH:9][NH:10][C:3]=12.ClC1N=C2N=CNC2=CC=1.[CH3:21][NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[CH:23]1([N:22]([CH3:21])[C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]=[CH:9][NH:10][C:3]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Clc1ccnc2nc[nH]c12
Reactant: CNC1CCCCC1
Agent: Clc1ccc2[nH]cnc2n1
Solvent: ClC(Cl)Cl
Product: CN(c1ccnc2nc[nH]c12)C1CCCCC1

Procedure:
To a 1:1 mixture (100 mg) of 7-chloro-1H-imidazo[4,5-b]pyridine and 5-chloro-1H-imidazo[4,5-b]pyridine was added N-methylcyclohexanamine (500 ul), and irradiated microwave at 200° C. for 2 hours. The reaction mixture was diluted with chloroform, washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography over NH-silica gel with a chloroform/EtOAc (100:1-100:5) as eluant to give N-cyclohexyl-N-methyl-1H-imidazo[4,5-b]pyridin-7-amine (54.8 mg) as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:33])[C:10]([NH:12][C@@H:13]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])=O)(C)(C)C.[ClH:34].CCOC(C)=O>>[NH2:8][C@@H:9]([CH3:33])[C:10]([NH:12][C@@H:13]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11].[ClH:34]
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)N)C(=O)OCc2ccccc2)cc1

Procedure:
A solution of (S)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-methoxyphenyl)propanoate (29.0 g, 63.6 mmol) in 3 N HCl-EtOAc (150 mL) was stirred for 1 h at ambient temperature. The mixture was concentrated and the residue was washed with petroleum ether (100 mL) to afford (S)-benzyl 2-((S)-2-aminopropanamido)-3-(4-methoxyphenyl)propanoate as an HCl salt (quant.), which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29]C)[CH2:20]1)[CH2:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH2:2][CH3:3].N1C=CC=CC=1.Cl>[NH4+].[OH-]>[CH2:1]([N:4]([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[OH:29])[CH2:20]1)[CH2:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH2:2][CH3:3]
Reactant: CCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCc2c(O)cccc2C1
Temperature: 200 °C

Procedure:
The product of Example 9 was combined with pyridine·HCl and heated to 200° C. in an oil bath and reaction was monitored by TLC. After completion, it was cooled, diluted with NH4OH and extracted with ether. The resulting oil was purified (Silica; 9:1 pet ether/EtOAc) and characterized by NMR (300 MHz). Anal. Calc. for C24H28N2O3 ·HCl: C, 76.36; H, 6.59; N, 6.54. Found: C, 67.17; H, 6.74; N, 6.34.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][OH:23])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-hydroxypropyl)pyrrolidine (17.1 g) in dichloromethane (170 ml) were added successively triethylamine (10.4 ml) and methanesulfonyl chloride (4.63 ml) under an ice-bath. The mixture was stirred at 0° C. for 1.5 hours and quenched by the addition of water (85 ml). The aqueous layer was separated and extracted with dichloromethane (50 ml×2). The organic layers were combined and washed with 1N hydrochloric acid (85 ml), brine (85 ml) and dried over magnesium sulfate. Evaporation of the solvent gave (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methanesulfonyloxypropyl)pyrrolidine (21.2 g) as a yellow paste.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH3:19])[C:16](=O)[C:15]([CH3:23])([CH2:21][CH3:22])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH:17]([CH3:19])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH3:23])[CH2:21][CH3:22]
Reactant: CCC1(C)CN(Cc2ccccc2)CC(C)C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CC(C)C1N
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 1-benzyl-3,5-dimethyl-3-ethyl-4-piperidone (3.0 g, 12.25 mmol) in methanol (40 ml) and stirring was continued for 20 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.8 g, 12.7 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 20 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1M sodium hydroxide solution (pH 9) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:44]=1[N:43]([CH3:45])[CH:42]=[CH:41]2)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:37]=[CH:38][CH:39]=[C:40]5[C:44]=4[N:43]([CH3:45])[CH:42]=[CH:41]5)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cn1ccc2cccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)c21
Agent: Cl
Product: Cn1ccc2cccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5[nH]cnc45)c3F)c21
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-methyl-1H-indole-7-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:25])C=CC=1)=O.II.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([I:25])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1n[nH]c2ccc(I)cc12
Yield: 35.1 %

Procedure:
A solution of Example 271A (300 mg; 1.7 mmol), bis(trifluoroacetoxy)iodobenzene (800 mg; 1.9 mmol), and iodine (253 mg; 1.0 mmol) in CH2Cl2 (10 mL) was stirred overnight at r.t., and treated with sodium bisulfite (aq). The precipitate was collected, rinsed with water and hexane, and dried under vacuum to provide the desired product (180 mg; 36%).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([CH3:39])[C:8]([CH2:10][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:17]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]2[C:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)=[N:18]1)=[O:9])=[O:5])C.[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[C:4]([CH2:6][N:7]([CH3:39])[C:8]([CH2:10][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:17]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]2[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)=[N:18]1)=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)CN(C)C(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(CC(=O)O)C(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 3-[2-{2-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)methyl-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (710 mg) in a mixture of dioxane (7 ml) and water (4 ml) was added 1N-aqueous sodium hydroxide solution (3.4 ml), which was stirred for two hours at room temperature. The reaction mixture was poured into ethyl acetate (100 ml) and aqueous layer was collected, which was adjusted to pH 1.5 with 6N-aqueous hydrochloric acid and extracted with ethyl acetate (100 ml×2). Organic layers were combined, washed in turn with water (50 ml×3) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (80 ml) eluting in turn with dichloromethane, 5%, 10%, 15% methanol in dichloromethane. Fractions containing desired product were collected. Evaporation of the solvent gave a residue, which was recrystallized from a mixture of dichloromethane and n-hexane to give 3-[2-{2-(N-carboxymethyl-N-methylcarbamoyl)methyl-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (300 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1>>[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([N:10]4[CH2:11][CH2:12][N:7]([C:2]5[N:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:8][CH2:9]4)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(c2ncccn2)CC1

Procedure:
Reaction of N-(2-pyrimidinyl)piperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g) analogously to the procedure of Example 4 gave the title compound as the hydrated dihydrochloride salt; yield 3.67 g (100%), m.p. 184°-187° C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](N)[C:13]=3[CH:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O)(=[O:22])C.N([O-])=O.[Na+].NC(N)=O>O>[C@@H:1]1([N:10]2[C:14]3[N:15]=[CH:16][NH:17][C:18](=[O:22])[C:13]=3[CH:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]cnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
A solution of one g of 7-β-D-arabinofuranosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4.3 ml of glacial acetic acid, 50 ml water, and 2.67 g of sodium nitrite is heated at 75° C. for one hour, cooled, and treated with 2.1 g of urea. The solution is evaporated in vacuo and the resulting residue is dissolved in water and treated with 15 ml of wet Dowex 50×8 (in hydrogen form). The resin is filtered and washed with water. The filtrate is treated with charcoal, filtered and evaporated in vacuo. The residue is recrystallized from water to provide 0.75 g of pure 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([NH:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(S)n[nH]1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(S)n[nH]1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a 2 l, 3-necked flask equipped with an efficient stirrer, reflux condenser, and thermometer was added 116 g (1.0 mole) of 5-amino-3-mercapto-1,2,4-triazole, 1 l of glacial acetic acid and 153 g (1.5 moles) of acetic anhydride. The mixture was heated to reflux (118°-120°) with stirring for 2 hours and then cooled to about 10° C. Recovery of the solids present by filtration and drying resulted in about 102 g (65 percent of theory) of the title compound, m.p. 326°-328° (dec.), a white, crystalline solid. A sample purified by washing with 2-propanol and drying melted at 336° C. (dec.). The carbon nmr spectrum of this compound was consistent with the assigned structure, having absorptions at 169.29, 164.99, 144.77, and 22.73 ppm as were the proton nmr spectrum, having an absorption at -2.00 ppm, and the elemental (C, H, and N) analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].Cl[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][Cl:40])=[CH:35][N:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][Cl:40])=[CH:35][N:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: ClCc1ccc(Cl)nc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(CCl)cn3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 21 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (106 mg, 0.25 mmol, see step (b) Example 12) and 2-chloro-5-chloromethylpyridine (41 mg, 0.25 mmol). Yield 90 mg (66%).
Reaction SMILES: O(CC([NH:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:16]([CH:19]3[CH2:23][CH2:22][CH2:21][S:20]3)[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[C:16]([CH:19]3[CH2:23][CH2:22][CH2:21][S:20]3)[CH2:17][S:18][C@H:13]12
Reactant: CC(C)(C)OC(=O)C1=C(C2CCCS2)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)C1=C(C2CCCS2)CS[C@@H]2[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
t-Butyl (6R, 7R)-7-phenoxyacetamido-3-(tetrahydrothien-2-yl)ceph-3-em-4-carboxylate (0.375 g), high Rf diastereoisomer in dry dichloromethane (5 ml) was cooled to -20° C. under argon and treated with N-methylmorpholine (0.175 g, 0.19 ml). A solution of phosphorous pentachloride (0.214 g) in dichloromethane (5.3 ml) was added. After 30 min. a sample showed no starting material (by i.r.). Methanol (3 ml) was added rapidly in one portion and then allowed to warm to room temperature. After 1 h water (5 ml) was added and the solution vigorously stirred for 30 min. The solvent was removed in vacuo and ethyl acetate added. The pH was adjusted to 7 with concentrated aqueous ammonia solution. Flash chromatography on silica gel with 50 and 60% ethyl acetate/hexane gave the more mobile diastereoisomer of the title compound as a pale yellow foam (0.104 g, 39%); (Found: M+, 342.1081. C15H22N2O3S2 requires M, 342.1072); νmax (CH2Cl2) 1776 and 1716 cm-1 ; δH (CDCl3) 1.56 (10H, s overlapping m), 1.79-1.99 (3H, m collapses to 1H, m on D20), 2.22-2.33 (1H, m), 2.42-2.53 (1H, m), 2.98 (2H, dd, J 4.0, 8.9 Hz), 3.36 and 3.74 (2H, ABq, J 17.9 Hz), 4.73 and 4.93 (2H, ABq, J 5.0 Hz) and 4.88 (1H, dd, J 6.5, 9.9 Hz). The second, more polar diastereoisomer of the title compound, was obtained as a pale yellow solid (0.079 g, 29%); (Found: M+, 342.1085. C15H22N2O3S2 requires M, 342.1072); νmax (CH2Cl2) 1777 and 1718 cm-1 ; δH (CDCl3) 1.57 (9H, s), 1.66-2.99 (4H, m collapses to 2H, m on D20), 2.03-2.14 (1H, m), 2.23-2.35 (1H, m), 2.96 (2H, dd, J 4.2, 8.6 Hz), 3.43 and 3.75 (2H, ABq, J 17.1 Hz), 4.69 and 4.96 (2H, ABq, J 5.0 Hz) and 4.79 (1H, dd, J 6.1, 9.9 Hz).