Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:3][CH:2]=1.ClC(OC)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].Cl>CCOCC.O.C(N(CC)CC)C>[CH2:18]([N:20]([CH2:21][CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]1[CH2:3][CH:2]=1)[CH3:19]
Reactant: CCNCC
Reactant: O=C(O)CCCCCCC1=CC1
Agent: COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)CCCCCCC1=CC1
Reaction time: 1.5 h

Procedure:
A solution of 7-cycloprop-1-enyl-heptanoic acid (0.25 g, 1.5 mmol) in 10 ml of ether was cooled in an ice bath and treated with 0.3 mL of triethyl amine. Methyl chloroformate (0.16 g, 17 mmol) was added, and the reaction was stirred for 1.5 hours. Excess diethylamine was added while the reaction was still cooled in an ice bath, and the reaction was stirred for one half hour. Additional ether and water were added, and the aqueous phase was acidified to pH 1 with aqueous HCl. The phases were separated, and the organic phase was washed with water, 1N sodium hydroxide, water and brine. The organic phase was dried over magnesium sulfate, filtered and stripped. Column chromatography gave 70 mg of colorless liquid 7-cycloprop-1-enyl-heptanoic acid diethylamide (Compound 48) in 74% purity.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].O1CCCC1.Br[CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH2:24]([CH:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH3:25]
Reactant: CC(=O)C1=CNCCC1
Reactant: CCCCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)CN1C=C(C(C)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was added under nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) and dry tetrahydrofuran (50 ml) stirring at room temperature. After one hour, 1-bromo-2-ethyl hexane (33.8 g, 0.175 mole) was added dropwise over 15 minutes and the mixture stirred overnight at room temperature. The reaction mixture was cautiously added to iced water (100 g) under nitrogen and extracted with diethyl ether (3×100 ml). The combined organic phase was dried over magnesium sulphate, concentrated under reduced pressure and the residue distilled to give methyl 1-(2-ethylhexyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (5) as a pale yellow oil (b.pt 140-142°C./0.1 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[CH2:10]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:16]1[CH:15]=[C:14]([C:11]2[CH2:10][CH:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:13][N:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(C2=NOC(c3c(Cl)cccc3Cl)C2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C2=NOC(c3c(Cl)cccc3Cl)C2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Iron powder (99 mg, 1.78 mmol) was added into a suspension of (±)-5-(2,6-dichlorophenyl)-3-(3-nitrophenyl)-2-isoxazoline (100 mg, 0.297 mmol) in ethanol/water (2/1) under nitrogen. The mixture was stirred for 10 min, followed by the addition of ammonium chloride (32 mg, 0.594 mmol). The reaction was stirred for 20 min at room temperature, followed by heating at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate to provide the title compound as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH2:21]([N:28]1[CH2:34][CH:33]2[NH:35][CH:30]([CH2:31][CH2:32]2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([N:28]1[CH2:34][CH:33]2[N:35]([CH2:11][C@H:9]([NH:10][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=3)[CH:30]([CH2:31][CH2:32]2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1
Reactant: c1ccc(CN2CC3CCC(C2)N3)cc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1C2CCC1CN(Cc1ccccc1)C2
Temperature: 60 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
tert-Butyl (2S)-2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (3 g, 11 mmol; see step (d) above) and 3-benzyl-3,8-diazabicyclo[3.2.1]octane (2.2 g, 0.011 mol; from Preparation B, step (e) above) were mixed in isopropanol (50 mL) and stirred at 60° C. for 48 h, and then at 80° C. for 2 h. The solvent was evaporated and the residue purified by chromatography, eluting with DCM/MeOH (9:1), to give the sub-title compound in 77% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[CH:9]2)([O-])=O.O.[NH2:19]N>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:14][CH3:15])=[C:7]([O:16][CH3:17])[CH:6]=2)[CH:11]=[CH:12][C:13]=1[NH2:19]
Reactant: NN
Reactant: COc1cc2cccc([N+](=O)[O-])c2cc1OC
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cc2ccc(N)c(N)c2cc1OC

Procedure:
5-Nitro-2,3-dimethoxynaphthalene (0.483 mmol) was dissolved in 4.0 ml of ethanol. The resulting solution was admixed with 0.18 ml of hydrazine hydrate and 18.5 mg of 10% palladium/carbon catalyst, and heated under reflux for 80 minutes. After cooling, the palladium/carbon catalyst was filtered off, and the filtrate was concentrated. The crude material thus formed was not purified further and was used as such for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7]C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.C([O-])(=O)C.[NH4+:22].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:7][C:6]1[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH2:22])=[O:9]
Reactant: COc1cc2c(=O)oc(=O)[nH]c2cc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(N)=O)c(N)cc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 67.5 %

Procedure:
476 mg (2 mmol) of 6-methoxy-7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione and 1.5 g (20 mmol) of ammonium acetate were dissolved in 20 ml of acetic acid and heated at 105° C. for 3 hours. The reaction mixture was then poured into ice-water and slowly brought to pH 7 with solid sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in vacuo. The crude product was triturated with diethyl ether, and the resulting precipitate was filtered off with suction. 285 mg (68%) of the desired product were obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.CC(C)=O>[N:13]1([C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Reactant: c1ccc2c(c1)CCCN2
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ncnc(N3CCCc4ccccc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (4 equivalents, Fluka, Buchs, Switzerland). M.p: 263-264° C.; FAB-MS: (M+H)+ =279 (corresponds to C17H18N4); Rf value (toluene-acetone--(4:6))=0.29.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 50 mg), potassium carbonate (138 mg), and morpholine (0.044 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 32 mg (yield 64%) of the title compound.
Reaction SMILES: C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+].[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21].[CH3:24]I>O.O1CCOCC1.CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([CH3:24])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: CI
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(F)cc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Sodium hydrogen carbonate (1.59 g, 18.87 mmol) and sodium sulfite (1.59 g, 12.58 mmol) were heated in water (10 mL) at 70° C. for 5 min. A mixture of 2-bromo-4-fluoro-benzene sulfonyl chloride (1.72 g, 6.29 mmol) in dioxane (15 mL) was added to the base solution and stirred at 70° C. overnight. The solvents were removed in vacuo, DMF (15 mL) and methyl iodide (0.43 mL, 6.85 mmol) were added and reaction mixture stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo, EtOAc (10 ml) added, washed with water (90 ml) and concentrated in vacuo to leave a colourless oil. The resulting oil was purified by flash chromatography (0-10% EtOAc in petroleum ether (40:60) followed by 100% MeOH) to afford 2-bromo-4-fluoro-1-(methylsulfonyl)benzene as an orange oil (1.3 g, 81%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), imidazole (1.70 g), potassium carbonate (2.80 g) and N,N-dimethylformamide (15 ml) was stirred at 130° C. for 2.5 hours. Water was added to the reaction mixture. The pH was then adjusted 6 with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolepropionic acid (1.35 g, 85%). This was recrystallized from methanol to give colorless needles. mp 194-195° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[CH3:31][N:32]([O:33][CH3:34])[C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Br)o1
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a suspension of 5-bromo-2-furancarboxylic acid (5.00 g) and N-hydroxysuccinimide (3.31 g) in acetonitrile (50 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (5.52 g) at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture was added a suspension of N,O-dimethylhydroxyl-amine hydrochloride (2.81 g) and triethylamine (10 ml) in acetonitrile (20 ml), and the mixture was stirred for 1 hour. To the reaction mixture were added 1,8-diazabicyclo-[5.4.0]-7-undecene (4.3 ml) and DMF (50 ml), and the mixture was stirred for 3 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:4→1:3→1:2) to give N-methyl-N-methoxy-5-bromofuran-2-carboxamide (2.77 g) as pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[F:24][C:22]1[CH:21]=[CH:20][C:19]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccc(OC)cc5)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-7-Fluoro-4-(4-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}acetic acid methyl ester (40.9 mg) is dissolved in tetrahydrofuran (4 mL) and 1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with aqueous 1 N hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.71 min; Mass spectrum (ESI−): m/z=447 [M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CCN(C(C)C)C(C)C.Cl[C:17]1[C:26]2[C:21](=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)CCC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:17]1[C:26]2[C:21](=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Reactant: CN(C)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(C)CCNc1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Temperature: 100 °C
Yield: 33.7 %

Procedure:
N,N-dimethylethylenediamine (0.10 ml, 0.95 mmol) and DIPEA (0.11 ml, 0.63 mmol) were added to a solution of N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (100 mg, 0.32 mmol) in n-butanol (1 ml) and the reaction was heated in a sealed tube at 100° C. for 16 h. After cooling, the mixture was concentrated in vacuo. The crude residue was purified by column chromatography with chloroform/MeOH (97:3) as the eluent to give the title compound (40 mg, 34%).
Reaction SMILES: O[CH:2]=[C:3]1CC2[C:5](=CC(C)=CC=2)[C:4]1=O.[NH:14]([CH2:16][CH:17]([OH:19])[CH3:18])[NH2:15].O.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:27][C:21]1[CH:26]=[CH:25][CH2:24][C:23]2[C:22]=1[CH:2]=[C:3]1[C:4]=2[CH:5]=[N:15][N:14]1[CH2:16][CH:17]([OH:19])[CH3:18]
Reactant: Cc1ccc2c(c1)C(=O)C(=CO)C2
Reactant: CC(O)CNN
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1=C2C=c3c(cnn3CC(C)O)=C2CC=C1
Yield: 93 %

Procedure:
A solution of 1.4 g (8.04 mmol) of 2-hydroxymethylene-6-methyl-1-indanone, 0.87 g (9.65 mmol) of (RS)-1-hydrazino-2-propanol and 100 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator for 2 hours. After concentration in a vacuum, the reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 4:1). 1.7 g (93%) of (RS)-1-(7-methyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol were obtained as a yellow oil which was used directly in the next reaction.
Reaction SMILES: [B:1]([F:4])([F:3])[F:2].CO.[C:7]([O:12][CH3:13])(=[O:11])[CH:8](C)[CH3:9].B(F)(F)F>>[C:7]([O:12][CH3:13])(=[O:11])[CH2:8][CH3:9].[CH2:7]=[CH2:8].[B:1]([F:4])([F:3])[F:2]
Reactant: COC(=O)C(C)C
Agent: FB(F)F
Solvent: CO
Product: C=C
Product: CCC(=O)OC

Procedure:
In still another approach, an admixture of BF3 /methanol/methyl isobutyrate in a molar ratio of 1:1:0.5 was introduced to the top of a countercurrent stripping column while nitrogen was passed through the bottom of the column under atmospheric pressure at a temperature of 80° C. The effort to preferentially strip the BF3 was unsuccessful. Analysis showed that no BF3 was removed by this technique. Methyl propionate is produced from ethylene and BF3.CH3OH.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]3([C:17]([S:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[N:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]3[OH:16])[CH:7]=[CH:6][C:5]=12.CC(C)([O-])C.[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>O1CCCC1>[CH2:36]([O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C:10]1([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)[C:17]([S:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[N:18][CH3:19])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1OCc1ccccc1
Temperature: -60 °C
Reaction time: 2.5 h
Yield: 39 %

Procedure:
1.04 g of 2-(imidazo[1,2-a]pyridin-6-yl)-2-((4-methoxybenzylthio)(methylimino)methyl)cyclohexanol was suspended in 25 ml of tetrahydrofuran. The obtained suspension was cooled to -60° C., followed by the addition of 300 mg of potassium t-butoxide at once. The obtained mixture was stirred at -60° C. for 2.5 hours, followed by the addition of 0.32 ml of benzyl bromide. The temperature of the obtained mixture was gradually raised to 0° C. in about one hour and the resulting mixture was stirred at 0° C. for 2 hours, followed by the addition of water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)] to give 500 mg of (yield: 39%). the title compound as a pale-yellow oil
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]([N:24]([CH:51]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:25][CH2:26][N:27]([CH2:38][CH2:39][C:40]2[C:48]3[S:47][C:46](=[O:49])[NH:45][C:44]=3[C:43]([OH:50])=[CH:42][CH:41]=2)C(=O)OCC2C=CC=CC=2)=[O:23])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>ClCCl.C(O)(=O)C>[CH2:1]([NH:8][C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]([N:24]([CH:51]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:25][CH2:26][NH:27][CH2:38][CH2:39][C:40]2[C:48]3[S:47][C:46](=[O:49])[NH:45][C:44]=3[C:43]([OH:50])=[CH:42][CH:41]=2)=[O:23])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(CCNCCC(=O)N(CCN(CCc2ccc(O)c3[nH]c(=O)sc23)C(=O)OCc2ccccc2)C2CCCCCC2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccc(CCNCCC(=O)N(CCNCCc2ccc(O)c3[nH]c(=O)sc23)C2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product from step iv) (0.106 g) was dissolved in dichloromethane (1.5 mL) and cooled to 0° C. Hydrobromic acid in acetic acid (33%, 0.6 mL) was added dropwise. The reaction mixture was stirred for 2 h then concentrated and azeotroped with toluene (×3) and methanol (×3). The crude material was purified by reverse phase HPLC (75-5% of 0.2% aqueous TFA in acetonitrile) to afford the product as a white solid (0.027 g).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:60]([C@H:9]1[CH2:10][CH2:11][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13])[CH2:8]1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (±)-cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (1.5 g, 6.93 mmol) (from Example 9a supra) and triphenylphosphine (1.99 g, 7.63 mmol) (Aldrich) in anhydrous tetrahydrofuran (60 mL) was added dropwise diethyl azodicarboxylate (1.2 mL, 1.32 g, 7.63 mmol) (Aldrich) at 0° C. Then after 2 minutes this was followed by the addition of diphenylphosphoryl azide (1.6 mL, 2.09 g, 7.63 mmol) (Aldrich) and the resulting solution was allowed to slowly warm up to room temperature. After stirring overnight the reaction mixture was partitioned between diethyl ether and water. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated and the residue was purified by chromatography on a silica gel column using a 0–20% diethyl ether in hexanes gradient to give (±)-trans-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane as a colorless liquid. (Yield 1.2 g, 72%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([NH2:22])[CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2.N1C=CC=CC=1>CS(C)=O.CO>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([NH:22][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: Nc1cc(Cl)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Solvent: CS(C)=O
Product: O=S(=O)(Nc1cc(Cl)cc2cccnc12)c1ccccc1
Yield: 60.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, benzenesulfonyl chloride (72 μl, 0.57 mmol), 6-chloroquinolin-8-ylamine (67 mg, 0.38 mmol) in pyridine (150 μl, 1.89 mmol) gave the title compound (73 mg, 61%) after trituration from DMSO/MeOH (1:2).