Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]([CH3:17])[CH2:15][N:14]([CH3:18])[NH:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:20]([O:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][C:43]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:47][CH2:46][NH:45][CH2:44]2)[CH2:37][CH2:36]1)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]([CH3:17])[CH2:15][N:14]([CH3:18])[NH:13]2)=[CH:8][C:4]=1[C:5]([N:45]1[CH2:46][CH2:47][C:43]([CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:26]3[N:25]([CH2:24][CH2:23][O:22][CH2:20][CH3:21])[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=3)[CH2:36][CH2:37]2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:44]1)=[O:7]
Reactant: COc1ccc(N2NN(C)CC2C)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(N5NN(C)CC5C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(3,5-dimethyl-4H-triazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].Cl[CH2:15][O:16][CH2:17][CH3:18].O>CN(C=O)C.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([O:13][CH2:15][O:16][CH2:17][CH3:18])([CH3:11])[CH3:12]
Reactant: CCOCCl
Reactant: Cc1cc(C(C)(C)O)c(Br)cc1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCOC(C)(C)c1cc(C)c(F)cc1Br
Temperature: 100 °C
Yield: 89 %

Procedure:
To a solution of 2-(2-bromo-4-fluoro-5-methylphenyl)propan-2-ol (2.0 g, 8.1 mmol) in DMF:DIPEA (2:1, 9 mL) was added (chloromethoxy)ethane (1.53 g, 16.2 mmol). The reaction mixture was heated at 100° C. in microwave equipment for 1.5 h. Water (200 mL) was added and the mixture was extracted with DCM (200 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (30:1) to give 1-bromo-2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylbenzene (2.2 g, 89%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.208-7.234 (m, 2H), 4.572 (s, 2H), 3.594 (q, J=7.0 Hz, 2H), 2.149 (s, 3H), 1.665 (s, 6H), 1.115 (t, J=7.0 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22]O)[C:11](=[O:26])[C@H:10]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][NH:34][S:35]([CH:38]1[CH2:40][CH2:39]1)(=[O:37])=[O:36].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCOC(C)=O.[Na+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:34]([CH3:33])[S:35]([CH:38]3[CH2:40][CH2:39]3)(=[O:37])=[O:36])[C:11](=[O:26])[C@H:10]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CNS(=O)(=O)C1CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
A flask, containing a solution of methyl 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)propanoate (195 mg, 0.408 mmol; Example 127, Step E) and N-methylcyclopropanesulfonamide (165 mg, 1.223 mmol) in toluene (2038 μL) was evacuated and backfilled with Ar (5×). Then cyanomethylenetributylphosphorane (321 μL, 1.223 mmol) was added. The light brownish orange mixture was heated to 70° C. for 2 h. More N-methylcyclopropanesulfonamide (134 mg, 0.991 mmol) was added and the mixture was heated to 70° C. for 2 h. The mixture was heated to reflux overnight and then cooled to room temperature. The mixture was diluted with EtOAc and sat. aq. NaCl solution. The layers were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4 g column eluent: 0 to 100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1.[OH2:15]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:1])=[O:15])=[CH:10][N:9]=1
Reactant: Cc1ccc(F)nc1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(F)nc1
Temperature: 100 °C

Procedure:
To the solution of KMnO4 (284 mg, 1.8 mmol) in H2O (50 mL) was added 2-fluoro-5-methylpyridine (100 mg, 0.9 mmol) at room temperature. The reaction mixture was then heated to 100° C. for 4 h. The resulting precipitate was filtered and discarded. The aqueous solution was washed with 3:2, hexane: ethyl acetate (2×20 mL), acidified with 2N HCl, then extracted with ethyl acetate (3×20 mL). The organic extracts were combined and washed with H2O and brine, dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to give 6-fluoronicotinic acid (30 mg) as a white solid. The title compound was prepared from 6-fluoronicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.09 (bs, 1H), 8.88 (d, J=2.4, 1H), 8.81 (d, J=9.3, 1H), 8.42-8.35 (m, 1H), 7.74 (d, J=3.3, 1H), 7.33-7.29 (m, 1H), 7.13-7.10 (m, 1H), 4.11 (q, J=7.2, 2H), 1.47 (t, J=7.2, 3H).
Reaction SMILES: N[C:2](=[CH:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7])[CH3:4].C([O-])(=[O:27])C.[NH4+]>C(O)(=O)C>[CH3:24][O:23][C:21]([CH2:20][C:2](=[O:27])[CH:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7])[CH3:4])=[O:22]
Reactant: COC(=O)C=C(N)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A mixture of biphenyl-4-carboxylic acid 2-amino-3-methoxycarbonyl-1-methyl-allyl ester (566 g, 1.74 mol, 1 eq) and ammonium acetate (283 g, 3.67 mol) in glacial acetic acid (11.3 L) was heated at reflux for 2 h, cooled, and concentrated. The residue was coevaporated with toluene (2×2.5 L) and EtOAc (2.5 L). The mixture was diluted with EtOAc (6.6 L) and transferred with EtOAc (2.2 L) to a bottom outlet separation flask. The mixture was washed twice with water (2.2 L), saturated aqueous NaHCO3 (1.1 L), and brine (2×2.2 L). The organic layer was dried (Na2SO4, 550 g), filtered with the aid of EtOAc (1.1 L), and concentrated. The residue was dissolved in isopropanol (2 L) at 50° C. and allowed to cool overnight at room temperature. The mixture was kept at 0° C. to 5° C. for 1 h. The precipitated solid was broken up and collected by filtration. The solid was washed with cold isopropanol (4×0.55 L) and dried overnight in a vacuum oven at 50° C. to yield 428 g of the title compound (72% from Step 2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:9][NH2:10])[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CN)CCC1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CNC2CCCC2)CCC1

Procedure:
Reaction of 1-aminomethyl-cyclobutanecarboxylic acid methyl ester with cyclopentanone, sodium acetate and sodium triacetoxyborohydride in DCM gave 1-cyclopentylaminomethyl-cyclobutanecarboxylic acid methyl ester
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:35]O>>[CH3:35][O:2][C:1]([CH2:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)CCc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(2-Carboxyethyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) is dissolved in methanol (50 ml) and thereto is added dropwise thionyl chloride (1.1 ml) under ice cooling. After adding, the mixture is stirred at 0°-5° C. for 1 hour and further at room temperature overnight. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane to give 1-{1-[4-(2-methoxycarbonylethyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.46 g) as white powder, m.p.: 85°-86° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([Br:11])=[CH:4][N:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:14])[C:6]=2[C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Brc1ncc(Br)c2[nH]ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1ccc2c(Br)ncc(Br)c21
Yield: 69.8 %

Procedure:
A mixture of 4,7-dibromo-1H-pyrrolo[3,2-c]pyridine (1.35 g), iodomethane (609 ul) and anhydrous potassium carbonate (1.35 g) in dry acetone (90 ml) was refluxed overnight. The mixture was evaporated and the residue added to ethyl acetate (60 ml) and water (60 ml). The organic layer was washed with water then brine, dried (MgSO4) and evaporated. Purification of the residue by chromatography on silica gel, eluting with dichloromethane, gave the title compound (0.99 g)
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH3:21]>Cl.C(O)C>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:25]1[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2
Reactant: CN(C)CCCN
Reactant: O=C(CC1CCCCCC1=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(Br)cc2)cc2c1CCCCC2

Procedure:
A mixture of 18.6 (0.06 mole) of 2-(p-bromophenacyl)cycloheptanone and 6.19 g (0.06 mole) of dimethylaminopropylamine is dissolved in 200 ml. of absolute ethanol. A few drops of concentrated hydrochloric acid are added and the mixture is refluxed for 4 hours. The ethanol is evaporated, and the residue is dissolved in dilute hydrochloric acid and washed with ether. The aqueous solution is basified with sodium carbonate solution and extracted with ether. The ether solution is washed with water, dried, and concentrated to a brown oil which solidifies upon cooling. The resulting solid is recrystallized from petroleum ether to give 1-(3-dimethylaminopropyl)-2-(p-bromophenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole, m.p. 69°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][S:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([NH:29][C:30]([NH:19][C:15]1[CH:14]=[C:13]([C:11]2[O:12][C:8]([S:7][CH2:6][C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][N:10]=2)[CH:18]=[CH:17][N:16]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1cc(-c2nnc(SCc3ccc(Cl)cc3)o2)ccn1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1cc(-c2nnc(SCc3ccc(Cl)cc3)o2)ccn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
A suspension of 4-[5-[(4-chlorobenzyl)thio]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (90 mg, 0.282 mmol) and benzyl isocyanate (187 mg, 1.41 mmol) in tetrahydrofuran (5 mL) was stirred at 70° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/chloroform/diethyl ether to give the title compound (72 mg, yield 56%) as colorless crystals.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].ClC1C(O)=C[C:10]2=[CH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N+:17]=3[CH:18]=[C:9]2C=1.O1C=CC(C(C2C=COC=2)=C)=C1>C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:13]1[C:12]2[N+:17](=[CH:18][CH:9]=[CH:10][CH:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cc2cc3cccc[n+]3cc2cc1Cl
Agent: C=C(c1ccoc1)c1ccoc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: c1cc[n+]2ccccc2c1
Reaction time: 6 h

Procedure:
A reaction mixture containing 8-chloro-9-hydroxybenzo[b]quinolizinium perchlorate (3.3 g; 10 mmol) and 1,1-di(3-furyl)ethylene (1.76 g, 11 mmol) in 50 ml of acetonitrile was allowed to reflux under nitrogen with stirring for 6 hours. The reaction mixture was concentrated in vacuo and the residue was crystallized from methylene chloride/ethyl acetate/methanol (7:2:1). The solid product was purified by silica gel chromatography (9:1 methylene chloride/methanol) to afford 3.3 g of 6,11-ethano-12,12-di(3-furyl)-9-chloro-10-hydroxy-6,11-dihydrobenzorb]quinolizinium perchlorate (Formula I: R1 =R2 =R3 =R4 =H; R5 =R6 =3-furyl; R7 =9-Cl; 10-OH; X- =ClO4-) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cc(Cl)ncc2[N+](=O)[O-])C1
Yield: 107.1 %

Procedure:
A solution of 2,4-dichloro-5-nitropyridine (from AstaTech, 0.500 g, 2.59 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (0.52 g, 2.6 mmol) and triethylamine (1.1 mL, 7.9 mmol) in isopropyl alcohol (10 mL) was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in EtOAc (40 mL) and washed with saturated aq. NaHCO3 and water (3×3 mL). The combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the sub-title compound (0.99 g), which was used in the subsequent reaction without further purification. LCMS (ESI) calc. for C15H22ClN4O4[M+H]+: m/z=357.1. found 357.0.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=2)(=[O:34])=[O:35])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Diisopropylethylamine (4.5 ml, 27.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 20.0 mmol) in DCM (40 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (6.0 g, 27.0 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, dried with diethyl ether and dried under vacuum give the title compound (7.14 g, 74% yield) as a pale yellow solid. Tr=2.07 min m/z (ES+) (M+Na+) 408.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:11]([CH3:12])=[N:10][N:9]2[CH:13]=[CH:14][CH:15]=[C:8]2[C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH3:2].[Cl:24]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:11]([CH3:12])=[N:10][N:9]2[C:13]([Cl:24])=[CH:14][CH:15]=[C:8]2[C:7]=1[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)Cc1c(C)nn2cccc2c1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of ethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (100 mg) in tetrahydrofuran (2 ml) was added N-chlorosuccinimide (43 mg) and the mixture was stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous ethyl acetate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (34 mg) as an yellow oil.
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[C:11]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(=[O:14])[CH2:12][CH3:13].O>CCCCCC.C1COCC1>[CH2:12]([C:11]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:1][O:14]1)[CH3:13]
Reactant: [Li]CCCC
Reactant: CCC(=O)c1ccncc1
Agent: C[S+](C)C
Agent: [I-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1(c2ccncc2)CO1
Temperature: 25 °C

Procedure:
n-Butyl lithium (7.3 cm3 of a 1.6M solution in hexane) was added at 0° to a stirred suspension of trimethyl sulphonium iodide (2.45 g) in THF (40 cm3) under nitrogen. After 5 minutes 4-propionylpyridine (1.35 g) in THF (5 cm3) was added, the mixture was allowed to warm to room temperature over 1.5 hours, water (20 cm3) was added and volatile material was removed in vacuo. The residue was partitioned between ether and water, the ethereal layer was dried (MgSO4) and evaporated and the residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give 2-ethyl-2-(4-pyridyl)oxirane as an oil (0.6 g). This material was taken without further purification into DMF (5 cm3) and treated with a solution of 2-sodioisothiazolidine-1,1-dioxide [made from isothiazolidine-1,1-dioxide (0.6 g) and sodium hydride (0.30 g of a 50% dispersion in oil)] in DMF (2 cm3) at 100° for 4 hours. Volatile material was removed in vacuo, the residue was partitioned between ethyl acetate (20 cm3) and water (10 cm3) and the aqueous phase was further extracted with ethyl acetate (2×20 cm3). The combined extracts were dried (MgSO4) and evaporated, and the residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to afford 2-[2-(4-pyridyl)-2-hydroxy]but-1-ylisothiazolidine-1,1-dioxide as an oil.
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:6]([O:17][CH3:18])=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[N+](=[CH2:21])=[N-]>O1CCCC1.CCOCC>[CH3:21][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[C:6]([O:17][CH3:18])=[CH:7][C:8]=1[O:14][CH2:15][CH3:16]
Reactant: C=[N+]=[N-]
Reactant: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid (13 g, 44 mmol) in tetrahydrofuran was cooled to 5° C. and treated with excess diazomethane in ether solution (prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) and stirred for 10 min. Solvent and excess diazomethane was removed by rotary evaporation. The resulting residue was dissolved in dichloromethane and filtered through a plug of silica gel and evaporated. The solids were triturated with ether/hexane to give 13 g of 5-chlorosulfonyl-2-ethoxy-4-methoxy-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][CH:6]=1.Cl.[NH2:10][OH:11]>N1C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]([CH:7]=[N:10][OH:11])=[CH:5][CH:6]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)s1
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 2-bromo-5-formylthiophene (2.5 mL, 21 mmol) and pyridine (25 mL) was added hydroxylamine hydrochloride (2.2 g, 32 mmol) on an ice bath, then, the solution was stirred overnight at room temperature. This reaction mixture was concentrated in vacuo, then, partitioned with water (50 mL), ethyl acetate (50 mL) then 1N hydrochloric acid solution (50 mL). The organic layer was separated, sequentially washed with an aqueous solution of saturated sodium bicarbonate and brine, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was washed with heptane-ethyl acetate (30:1), and the title compound (4.3 g, 21 mmol, 98%) was obtained as a light brown solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[CH3:15][NH:16][CH2:17][C@@H:18]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26]O)[OH:25])[OH:23])[OH:21])[OH:19]>C(O)C>[CH3:15][N:16]([CH2:17][C@H:18]([OH:19])[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@H:24]([OH:25])[CH3:26])[C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([N:16]([CH3:15])[CH2:17][C@H:18]([OH:19])[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@H:24]([OH:25])[CH3:26])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Solvent: CCO
Product: C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CN(C)C(=O)c1cnc(C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@@H](C)O)cn1
Yield: 102 %

Procedure:
A solution of 392 mg of 2,5-dimethoxycarbonylpyrazine and 780 mg of N-methylglucamine in 5 cm3 of ethanol is heated at a temperature close to the reflux temperature for 3 hours and the reaction mixture is filtered while hot. The white solid is washed with twice 10 cm3 of boiling ethanol. 1000 mg of N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5-tetrahydroxy-1-hexyl]-N′-methyl-N′-[(2S,3R,4R,5R)-2,3,4,5-tetrahydroxy-1-hexyl]-pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 152° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, at a temperature of 403 K, δ in ppm): 3.14 (s, 6H: 2×NCH3); from 3.45 to 4.28 (mts, 16H: 8×CHO−2×CH2 and 2×CH2N); 8.78 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:16]1[C:21]([S:22](Cl)(=[O:24])=[O:23])=[CH:20][CH:19]=[C:18]([I:26])[CH:17]=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:22]([C:21]1[CH:16]=[CH:17][C:18]([I:26])=[CH:19][CH:20]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: CCOCCN
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
2-Ethoxyethylamine (2.14 g, 24 mmol) and diisopropylethylamine (4.2 ml, 24 mmol) were dissolved in DCM (50 ml) and cooled to 0° C. To this was added pipsyl chloride (6.05 g, 20 mmol) in portions and the reaction stirred for 18 hours. Volatiles were evaporated in vacuo. The residue was dissolved in EtOAc (50 ml), extracted 1N citric acid (2×50 ml), brine (50 ml), dried and evaporated in vacuo to yield an oil which solidified on standing to give the title compound as a pale yellow solid (6.97 g, 98%). NMR: 1.01 (t, 3H), 2.89 (q, 2H), 3.30 (m, 4H), 7.53 (d, 2H), 7.75 (t, 1H), 7.97 (d, 2H); m/z 354 (M−H)−.