Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[H-].[Na+].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12
Reactant: N#Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2ccc(C#N)c([N+](=O)[O-])c2)c2nccc(Cl)c12
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Compound (6b) (0.335 g) was dissolved in DMF (8.6 mL), and sodium hydride (0.097 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 4-fluoro-2-nitrobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration and washed by sprinkling water to obtain 4-{4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.5 g, 85%). 4-{4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.35 g) and ammonium chloride (0.35 g) were dissolved in a solvent mixture of THF (3 mL), methanol (3 mL), and water (3 mL). Iron (0.57 g) was added to the resulting solution, followed by stirring at 70° C. for 1 hr. Insoluble matters were filtered by celite, and the solvent was distilled away. The precipitate was washed with water and was collected by filtration to obtain compound (106a) (0.32 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)Cl.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(Br)cc1
Product: COC(=O)c1nc(C)sc1-c1ccc(Br)cc1

Procedure:
prepared by reaction of 3-(4-Bromo-phenyl)-3-chloro-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=312.2.
Reaction SMILES: [C:1]([O:4][CH2:5]C)(=[O:3])[CH3:2].[CH3:7][CH2:8][CH2:9][CH2:10]CC.C([O:15]CC)C>ClCCl>[O:15]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:2][C:1]([O:4][CH3:5])=[O:3]
Reactant: CCOCC
Reactant: CCCCCC
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCCCC=O
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Pyridinium chlorochromate (16.27 g, 75.48 mM) was dissolved in dichloromethane (140 ml), and a solution of methyl 6-hydroxy-hexanoate (10.03 g, 68.61 mM) obtained in Preparation Example 3-1 dissolved in dichloromethane (20 ml) was added dropwise thereto for 30 min. The resulting mixture was stirred at 25˜30° C. for 2 hrs. After the completion of reaction, the reaction mixture was diluted with ethyl ether, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to obtain 5.77 g of the title compound (yield 59%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([NH2:19])=O)=[C:14]([I:16])[N:15]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C[N:22]([CH:24](OC)OC)C.O.[NH2:30]N>C1(C)C=CC=CC=1.O>[I:16][C:14]1[N:15]=[C:11]([C:9]2[C:8]([CH3:20])=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=2)[O:12][C:13]=1[C:17]1[N:22]=[CH:24][NH:30][N:19]=1
Reactant: CC(=O)Nc1cc(-c2nc(I)c(C(N)=O)o2)c(C)cn1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(I)c(-c3nc[nH]n3)o2)c(C)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a slurry of 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-1,3-oxazole-5-carboxamide (12.0 g, 31.0 mmol) in toluene (240 mL) was added DMF-DMA (24.0 mL, 187 mmol). The reaction mixture was allowed to stir at 90° C. for 5 h and then concentrated. The residue was suspended in AcOH (120 mL) and hydrazine hydrate (4.8 mL, 155 mmol) was added slowly. The reaction mixture was allowed to stir at rt overnight and then diluted with water. The slurry was filtered and the solid was collected, washed with water, and dried to give N-{4-[4-iodo-5-(1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (12.5 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:12]([OH:16])[CH2:13]CC.[Br:17]Br.CC1C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C(O)CO>[Br:17][CH2:10][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Br:1])[CH:3]=2)[O:16][CH2:12][CH2:13][O:11]1
Reactant: BrBr
Reactant: CCCCO
Reactant: CC(=O)c1ccc(C)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: OCCO
Product: Cc1ccc(C2(CBr)OCCO2)cc1Br
Yield: 57 %

Procedure:
To a stirred and hot (50° C) solution of 64 parts of 1-(3-bromo-4-methylphenyl)-1-ethanone in 160 parts of 1-butanol are added dropwise, during a 1 hour-period, 48 parts of bromine without external heating. After stirring for 1 hour at room temperature, there are added successively 21.7 parts of 1,2-ethanediol, 6 parts of 4-methylbenzenesulfonic acid and 720 parts of benzene and the whole is stirred and refluxed overnight with water-separator. The reaction mixture is evaporated and the residue is taken up in 2,2'-oxybispropane. The resulting solution is washed successively once with a diluted sodium hydroxide solution and three times with water, dried, filtered and evaporated. The residue is distilled, yielding 57 parts (57%) of 2-(bromomethyl)-2-(3-bromo-4-methylphenyl)-1,3-dioxolane; bp. 126°-130° C. at 0.1 mm. pressure.
Reaction SMILES: C[C@H]1CCCN1.C[C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[N:9]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:10][CH2:11][CH2:12][CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Agent: C[C@H]1CCCN1
Product: C1CCN([C@@H]2CCNC2)C1

Procedure:
By use of (S)-2-methyl-pyrrolidine in the substitution reaction step (2S,3′S)-2-methyl-[1,3′]bipyrroldinyl is obtained.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([SiH2:11][O:12][C:13]([CH3:32])([CH3:31])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:30])[C:21]2[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=2)[C:26]#[N:27])=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[NH+]1C=CC=CC=1.C1(C)C(S([O-])(=O)=O)=CC=CC=1>ClCCl>[C:7]([SiH2:11][O:12][C:13]([CH3:32])([CH3:31])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:30][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:21]2[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=2)[C:26]#[N:27])=[CH:18][CH:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(O)c2ccc(F)c(C#N)c2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(OC2CCCCO2)c2ccc(F)c(C#N)c2)cc1
Yield: 97.8 %

Procedure:
Add 3,4-dihydro-2H-pyran (0.340 g, 4.04 mmol) to a solution of 5-{[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-hydroxy-methyl}-2-fluoro-benzonitrile (1.00 g, 2.69 mmol) and pyridiniuM-toluenesulfonate (0.068 g, 0.269 mmol) in dichloromethane (0.2M). Stir the reaction for 3 h at room temperature. Evaporate solvent and filter through a short pad of silica gel. The title compound (1.20 g, 2.63 mmol, 98%) is taken directly onto the next step (Preparation 58). MS (m/z): 456 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: COC(=O)CCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)CCc1cccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)c1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and 3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH2:18]=O.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:21][SH:22]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[C:14]([N+:15]([O-:17])=[O:16])[CH2:18][S:22][CH2:21][C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CS
Reactant: C=O
Solvent: CCO
Product: CCOC(=O)CSCC(=C1NCCN1Cc1ccc(Cl)nc1)[N+](=O)[O-]
Yield: 77.7 %

Procedure:
0.22 g of 1-(6-chloro-3-pyridylmethyl)-2-nitromethyleneimidazolidine, 0.08 g of 37% formaldehyde aqueous solution and 0.1 g of ethyl thioglycolate were added to 5 ml of ethanol, and were reacted under reflux for 3 hours. After completing the reaction, ethanol was distilled off under reduced pressure, and a small amount of ethyl acetate was added to the residue thus obtained to filter the insoluble materials out, thus obtaining 0.25 g of the aimed product (Compound No. 1) having a melting point of from 122.8° to 124.3° C. wherein i is 1, can be obtained, and when the oxidizing agent is used in a molar amount of two times as large as the compound having the formula (I-1), the compound having the formula (I-2) wherein i is 2, can be obtained. (iii) When Z is an alkyl group or an acyl group: ##STR13## (wherein X, Y and j are as defined above; Z' is an alkyl group or an acyl group; and Q is a halogen atom or an acid residue).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:11])[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic acid (0.70 g, 1.44 mmol) was added 4-dimethylaminopyridine (0.26 g, 2.16 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.42 g, 2.16 mmol), methanesulfonamide (0.15 g, 1.58 mmol) and triethylamine (0.40 mL, 2.88 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 1 M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.34 g, LRMS: 526.2).
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[CH2:4][CH2:5][C:6]2([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]=1[C:13]1[C:8](=[C:9]([Cl:17])[C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.[Cu][C:24]#[N:25]>CN1CCCC1=O>[CH2:18]([C:6]12[CH2:5][CH2:4][C:3](=[O:22])[C:2]([C:24]#[N:25])=[C:14]1[C:13]1[C:8](=[C:9]([Cl:17])[C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2)[CH2:19][CH2:20][CH3:21]
Reactant: N#C[Cu]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)c(Cl)c1C2
Solvent: CN1CCCC1=O
Product: CCCCC12CCC(=O)C(C#N)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 150 °C
Yield: 73.5 %

Procedure:
A solution of 4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (103 mg, 0.268 mmol) in anhydrous 1-methyl-2-pyrrolidinone (0.54 mL) was treated with copper(I) cyanide (24 mg, 0.268 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 150° C. for 1.5 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (5×50 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil. The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 5% EtOAc in CH2Cl2. The product band was eluted with EtOAc and the eluent evaporated under vacuum to afford 9a-butyl-8-chloro-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (65 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34]OS(C)(=O)=O)[O:13][CH:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40].[Mg+2].[I-].O>CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34][I:40])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40]
Reactant: COC1O[C@H](CCOS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: O
Product: CO[C@H]1O[C@H](CCI)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-D-glucoheptopyranoside (0.38 g, 0.83 mmol) in ether (5 mL) was added at 0° C. a 0.375 M solution of magnesium iodide (6.7 mL). The mixture was stirred 15 min at 0° C. The excess of magnesium iodide was hydrolyzed with water. The reaction mixture was washed with sodium thiosulfate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 2:8 mixture of ethyl acetate and hexane afforded the expected iodide methyl 2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranoside which was crystallized from hexane (0.368 g, 91%); m.p. 66°-68° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:12]=[N:13][CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cncc1-c1ccc([N+](=O)[O-])cc1
Yield: 62.6 %

Procedure:
Reaction of 4-(4-nitrophenyl)-1H-imidazole (160 mg, 0.85 mmol), NaH (60%, 33 mg, 0.82 mmol), and SEMCl (158 uL, 0.89 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (170 mg, 65%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 3.55 (t, 2H, J=7.5 Hz), 5.33 (s, 2H), 7.50 (s, 1H), 7.69 (s, 1H), 7.94 (d, 2H, J=6.0 Hz), 8.26 (d, 2H, J=6.0 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[CH3:26])(=[O:18])=[O:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH3:26][C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[S:16]([N:11]1[CH:10]2[CH:13]([CH2:14][CH2:15][NH:8][CH2:9]2)[CH2:12]1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)c(C)c1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)N2CC3CCNCC32)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8-(2,4-dimethyl-benzenesulfonyl)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester in dioxane (8 mL) was added trifluoro acetic acid (3 mL), the reaction mixture was stirred for 16 h at room temperature. The solvent and the excess of trifluoro acetic acid were removed under reduced pressure. The resulting trifluoro acetic acid salt of the title compound was used crude without further purification (150.0 mg, 49%). MS (ESI) mass calcd. for C14H20N2O4S, 280.39; m/z found, 281.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][N:3]=1.[NH2:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CS(C)=O.O>[NH2:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][N:3]=2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Reactant: N[C@H]1CCNC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A solution of compound 94 (1.00 g, 2.88 mmol) and 3-(S)(−)aminopyrrolidine (495 mg, 5.75 mmol) in DMSO (5 ml) was heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature and stirred for an additional 16 h and diluted with water. The aqueous solution was extracted with AcOEt/dichloromethane mixture, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound 153 as an orange solid (981 mg, 86% yield). 1H NMR: (DMSO) δ (ppm): 8.76 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.70-3.53 (m, 4H), 3.26 (dd, J=11.3, 3.9 Hz, 1H), 2.07-1.98 (m, 1H), 1.75-1.67 (m, 3H), 1.29 (t, J=7.0 Hz, 3H). LRMS (ESI): (calc.) 397.2; (obt.) 398.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]([C:27]1[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=1)[S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=O)C(C)C>CO.C(COC)OC>[CH3:34][O:33][C:32]1[C:27]([NH:10][S:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[N:28][CH:29]=[C:30]([CH3:35])[N:31]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(C)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
2M Sodium hydroxide solution (0.6 ml) was added to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.232 g) in methanol (2.4 ml) and dimethoxyethane (2.4 ml) and the mixture was stirred for 2 hours. Volatile material was removed by evaporation and water (10 ml) was added to the residue. The mixture was acidified with 2M hydrochloric acid and extracted with ethyl acetate (2×10 ml). The extracts were washed with water (10 ml) and saturated sodium chloride solution (10ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethanol to give N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.1 g) m.p. 184°-185° C.; 1H NMR (d6 -DMSO): 2.3 (s,3H), 2.4 (s,3H), 3.6 (s,3H), 7.05-7.3 (m,5H), 7.45-7.7 (m,3H), 8.1 (dd,1H), 9.35-9.45 (br s,1H); mass spectrum (-ve FAB, DMSO/Methanol/GLY): 368 (M-H)-.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[S:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16]1COC[CH2:17]1>ICC>[CH2:16]([S:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=2[N:9]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Dissolve 5-nitro-3H-benzooxazole-2-thione (10.58 g, 53.9 mmol) in anhydrous THF (300 mL). Cool the mixture to 0° C. in an ice bath. Add NaH (4.90 g, 60% dispersion in mineral oil) slowly. Stir the resulting mixture at 0° C. for 10 min. Add iodoethane (20.0 mL, 0.250 mmol) to the stirring mixture. Allow the mixture to warm to room temperature and stir overnight. Adsorb the reaction mixture onto silica gel and subject to flash column chromatography in 2 batches (330 g, 120 g columns, eluting with 10-50% ethyl acetate/n-hexane both times) to yield the desired product (4.93 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, J=2.4 Hz, 1H), 8.23 (dd, J=9.2, 2.6 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 3.37 (q, J=6.8 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.O.[CH3:22]N(C=O)C>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][NH:12][CH:22]=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c2c[nH]nc2n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(Cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione (5 g) was dissolved in DMF (5 mL) followed by addition of POCl3 (4 mL) dropwise at 0° C. The reaction was warmed to 80 C. for 3 h, followed by stirring at RT overnight. The solution was added to 200 mL of water and filtered to give about 5 g of yellow solids. Proton NMR was sufficient to carry on to next step.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-2-furoic acid (247 mg, 1.29 mmol) was coupled to aniline (124)(250 mg, 1.29 mmol) using Method C to give the title compound.
Reaction SMILES: P(OP(O)=O)(O)=O.C(C(C(C)C)(C(C)C)C(C)C)(C)C.[CH2:21]1[C:29]2[C:25](=[CH:26][C:27]([P:40]([O:46]C(C)C)(=[O:45])[O:41]C(C)C)([P:30]([O:36]C(C)C)(=[O:35])[O:31]C(C)C)[CH:28]=2)[CH:24]=[CH:23][NH:22]1.ClCC1C=NC=CC=1CCl>>[CH2:21]1[C:29]2[C:25](=[CH:26][C:27]([P:30]([OH:35])(=[O:31])[OH:36])([P:40]([OH:46])(=[O:41])[OH:45])[CH:28]=2)[CH:24]=[CH:23][NH:22]1
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)C=C2C=CNCC2=C1
Agent: CC(C)C(C(C)C)(C(C)C)C(C)C
Agent: ClCc1ccncc1CCl
Agent: O=[PH](O)O[PH](=O)O
Product: O=P(O)(O)C1(P(=O)(O)O)C=C2C=CNCC2=C1

Procedure:
Using essentially the same procedure as in Example 1(a), tetraisopropyl methane diphosphonate is converted to tetraisopropyl dihydro-2-pyrindine-6,6-diphosphonate by reaction with 3,4-bis(chloromethyl)pyridine. The resulting ester is hydrolyzed as in Example 1(a) to yield dihydro-2-pyrindine-6,6-diphosphonic acid. The dihydro-2-pyrindine-6,6-diphosphonic acid is then converted to the octahydro-2-pyrindine-6,6-diphosphonic acid by a hydrogenation procedure which is essentially the same as in Example 1(b). Substituted octahydro-2-pyrindine-6,6-diphosphonic acid compounds are prepared as described hereinbefore in Example 1 by using as the starting material the appropriately substituted 3,4-bis(chloromethyl) pyridine.