Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[C:13]([CH3:23])([O:18][Si](C)(C)C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[C:13]([OH:18])([CH3:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O[Si](C)(C)C)CN(C(=O)OCc2ccccc2)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OCc2ccccc2)CCC1=O

Procedure:
The thus-obtained N-benzyloxycarbonyl-3-methyl-3-trimethylsilyloxy-4-piperidone is dissolved in THF (450 mL) and concentrated hydrochloric acid (50 mL) is added. The resultant solution is stirred at 23° C. for 24 h and concentrated to an oily residue. The residue is suspended in a saturated sodium bicarbonate solution (250 mL) and the resultant suspension is extracted with ether (2×100 mL). The organics are combined, dried (MgSO4), filtered and concentrated to give crude N-benzyloxycarbonyl- 3 -hydroxy-3-methyl-4-piperidone as an oil: 17.2 g.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([O:23]CC)=[O:22].CO.O>C1COCC1>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Lithium hydroxide (0.113 g, 4.72 mmol) was added to a solution of ethyl 3-bromo-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.181 g, 0.472 mmol) in THF:methanol:water/3:1:1 (5 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in water, acidified with 1 N aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.151 g, 77%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (br. s., 1H), 9.27 (br. s., 1H), 7.73 (br. s., 1H), 7.22-7.33 (m, 2H), 1.44-1.54 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[N:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH2:3]1.N>[Ni].C(O)C>[NH2:16][CH2:15][C:12]1[CH:13]=[N:14][C:9]([S:8][CH:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:17])([CH3:1])[CH2:3]2)=[CH:10][CH:11]=1
Reactant: CC1(C)CCCC(Sc2ccc(C#N)cn2)C1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC1(C)CCCC(Sc2ccc(CN)cn2)C1
Yield: 53.2 %

Procedure:
To a slurry of Raney Nickel (0.2 g, 50% in water) in ethanol (35 mL) add a solution of 6-[(3,3-dimethylcyclohexyl)thio]-pyridine-3-carbonitrile (0.37 g, 1.5 mmol) in ethanol (5 mL) followed by aqueous ammonia (0.88 M, 2 mL) and hydrogenate the mixture in a Parr shaker at 60 psi for 3 h. Filter the mixture through Celite® washing the filter cake with ethanol. Remove the solvent in vacuo to obtain the title compound as an oil (0.2 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(NC(=O)c2cc(Cl)ccn2)CC1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN1CCC(NC(=O)c2cc(Oc3ccc(N)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.557 g, 5.06 mmol) in DMA (8.5 mL) was treated with potassium tert-butoxide (0.639 g, 5.69 mmol), stirred at RT for 1 h, treated with a solution of 4-chloro-N-(1-methylpiperidin-4-yl)picolinamide (1.07 g, 4.22 mmol) in DMA (8.5 mL) and stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM/NH4OH) to afford 4-((6-aminopyridin-3-yl)oxy)-N-(1-methylpiperidin-4-yl)picolinamide (0.654 g, 47%). 1H NMR (400 MHz, DMSO-d6): δ 8.49-8.48 (m, 2H), 7.81 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 6.52 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 3.69 (d, J=9.9 Hz, 1H), 2.69 (d, J=11.1 Hz, 2H), 2.13 (s, 3H), 1.93 (t, J=11.2 Hz, 2H), 1.68-1.62 (m, 4H); MS (ESI) m/z: 328.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:17]1([CH3:28])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:28])[CH:13]=[N:12]1
Reactant: Cc1ccccc1/C=C/C(=O)O
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2ccccc2C)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@H:8]([C@H:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[C:9](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:10].O>C1COCC1>[CH3:7][C@H:8]([C@H:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[CH2:9][OH:10]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)CO
Reaction time: 3 h
Yield: 100 %

Procedure:
A 1M THF solution of LAH (95.9 mL, 95.9 mmol) was added to (R)-3-((2R,3R)-2,3-dimethyl-hexanoyl)-4-phenyl-oxazolidin-2-one in THF (300 mL) under nitrogen at −78° C. and stirred for 3 hours at that temperature. Water was added dropwise to quench the excess LAH and the solution was poured into a mixture of ice and ether. The mixture was extracted into ether, washed with water and dried over MgSO4. The solution was concentrated followed by the addition of excess hexane. The resulting white precipitate was filtered and washed with haxane. The filtrate was concentrated to afford the titled compound (5.05 g, 100% yield) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 9 H) 1.0 (d, J=6.8 Hz, 1 H) 1.1 (m, 1 H) 1.2 (m, 3 H) 1.6 (m, 2 H) 3.4 (m, 1 H) 3.6 (m, 1 H).
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:30])[CH:9]=1>CO>[ClH:1].[ClH:1].[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:30])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC2CCNCC2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(OC1CCNCC1)N1CCNCC1COc1cccnc1
Reaction time: 16 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 4-tert-butyl 1-piperidin-4-yl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (101.5 mg, 0.241 mmol) in MeOH (1 mL). After 16 h, the reaction mixture was concentrated under reduced pressure, yielding 103.3 mg (99%) of the desired product. LC-MS: RT=1.26 min, [M+H]+=321.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCOCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with morpholine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH4+].[Cl-]>CO.CC(C)=O>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(C)=O
Product: Nc1ccc(Cl)nc1Cl

Procedure:
4 g of 2,6-dichloro-3-nitropyridine are added to a suspension of 8 g of reduced iron in 200 cm3 of a water/alcohol (50/50) solution containing 1.6 g of NH4Cl. The suspension is brought to reflux for 1 hour. The insoluble material is then removed by filtration. The filtrate is treated with 0.4 g of Na2SO3 and 0.4 g of NaH2PO2. The solution is adjusted to a pH of 8 and the alcohol is concentrated under reduced pressure until precipitation. The crystals corresponding to 3-amino-2,6- dichloropyridine are collected on a filter, washed with water and dried.
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17]>CC(C)=O>[CH2:1]([N:5]1[CH2:6][CH:7]2[C:13]([CH3:14])([CH3:15])[CH:11]([CH2:10][N:9]([C:20]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])[CH2:8]2)[CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: CCCCN1CC2CN(c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CC(C1)C2(C)C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A solution of 4.7 g 7-(n-butyl)-9,9-dimethyl-3,7-diazabicyclo [3.3.1]nonane in 10 ml acetone was added dropwise to a solution of 4.2 g 2,4-dinitrofluorobenzene in 40 ml acetone with stirring. Stirring of the reaction mixture was continued at room temperature and the mixture was left to stand overnight. Then acetone was withdrawn and aqueous citric acid solution was added to the residue and this mixture was extracted twice with ethyl acetate. For further working-up, the aqueous residue was rendered alkaline with dilute sodium hydroxide solution. This mixture was again extracted twice with ethyl acetate. The combined organic phases were dried with magnesium sulfate and reduced. The residue was recrystallised from ether/hexane. 5.5 g 7-(n-butyl)-3-(2,4-dinitrophenyl)-9,9-dimethyl-3,7-diazabicyclo-[3.3.1]nonane with a melting point of 119° C. were obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:56](O)=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:56](=[O:57])[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Product: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Yield: 53.8 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(Nα,Nε -dibenzyloxycarbonyl-L-lysylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (420 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of Nα,Nε -dibenzyloxycarbonyl-L-lysine (608 mg) according to a similar manner to that of Example 5, mp. 150°-157° C. (dec.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)C1C=CC=CC=1>C(O)(C)C.[Pd].Cl>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5-(4-benzylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (1.00 g) in isopropanol was added to 10% palladium on charcoal (265 mg) pretreated under hydrogen in hydrochloric acid, and the resulting mixture was stirred under hydrogen at room temperature for 12 hours. After elimination of the catalyst by filtration, the filtrate was evaporated. The residue was neutralized with 10% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was washed with water, dried and evaporated to afford 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene as oily material. M.P., 221°-224° C. (oxalate).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Si]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:48]([CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[C:47]3[CH:55]=[CH:56][C:57]([C:59]4[NH:63][N:62]=[N:61][N:60]=4)=[CH:58][C:46]=3[N:45]=2)=[CH:40][CH:39]=1)(C(C)(C)C)(C)C.C(OCC)(=O)C>CN(C=O)C.O>[OH:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[N:48]([CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[C:47]3[CH:55]=[CH:56][C:57]([C:59]4[N:60]=[N:61][N:62]([C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[N:63]=4)=[CH:58][C:46]=3[N:45]=2)=[CH:42][CH:43]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnn[nH]4)ccc3n2C2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2nc3cc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)ccc3n2C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
Trityl chloride (4.57 g, 0.0164 mol) and N,N-diisopropylethylamine (2.42 g, 0.0187 mol) were added to a stirred mixture of compound 21 (7.4 g, 0.0156 mol) in DMF (36 mL). The mixture was stirred for 18 h at an oil bath temperature of 70° C. The mixture was cooled and poured into a mixture of ethyl acetate and water to precipitate the fully protected benzimidazole, 2-[4-(tert-butyldimethylsilyoxy)phenyl]-1-cyclohexyl-5-[2-(trityl)-2H-tetrazol-5-yl]-1H-benzimidazole. The solid was collected, washed with cold water and dried to afford the protected benzimidazole as a colorless solid (9.1 g, 81% yield). ESI-MS m/e 717 (M+1). HPLC purity (uv) 94%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28]S(C)(=O)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:33]1[C:38](O)=[CH:37][CH:36]=[C:35]([CH3:40])[CH:34]=1>CN(C)C=O>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:38]2[CH:37]=[CH:36][C:35]([CH3:40])=[CH:34][CH:33]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 27.6 %

Procedure:
Potassium carbonate (8.09 g) was added to a solution of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate (11.1 g), which is the product of Reference example 35(a), and p-cresol (2.85 g) in N,N-dimethylformamide (110 ml). This mixture was stirred at 70° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel column using hexane/ethyl acetate=9/1 as the eluant to afford the desired compound (2.84 g) as a colorless oil.
Reaction SMILES: C(Cl)C=C(C)C.[OH-:7].[Na+].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.[Cl-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCC.O.CC(C)=O>[CH3:9][CH2:10][C:11](=[O:7])[CH:12]=[CH:13][CH2:14][CH2:15][CH3:16]
Reactant: [OH-]
Reactant: CCCCCCCCCC
Agent: CC(C)=CCCl
Agent: CCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: CCCC=CC(=O)CC
Yield: 51 %

Procedure:
By using the same reaction vessel as used in Example 1, 10.45 g of prenyl chloride, 34.8 ml of acetone, 20.3 g of a 65 % aqueous caustic soda solution, 5 ml of n-decane and 0.264 g of lauryl trimethylammonium chloride were added into the vessel, and then the mixture was allowed to react for 12 hours at 30°C. with vigorous stirring. After the reaction was completed, 40 ml of water was added to the resultant solution to dissolve the sodium chloride. Methyl heptenone was produced as determined by using gas chromatography and the yield was 51 % calculated on the theoretical value.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(Cl)Cl.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16](O)[C:17]([CH3:35])([CH3:34])[N:18]=[C:19]2[C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>O>[F:7][CH:16]1[C:15]2[C:20](=[CH:21][CH:22]=[CH:23][C:14]=2[F:13])[C:19]([C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18][C:17]1([CH3:35])[CH3:34]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1O
Solvent: O
Solvent: ClCCl
Product: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1F
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Diethylaminosulphur trifluoride (76 mg) was added to an methylene chloride (20 mL) solution of 3-(5-fluoro-4-hydroxy-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (50 mg, 0.16 mmol), followed by stirring for 1 hour under ice cooling, pouring water, extracting with ethyl acetate, and applying the resulting residue to chromatography to obtain 45 mg (yield 90%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14]CC)=[O:13])=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc2ccc(Cl)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of ethyl 2-chloroquinoline-7-carboxylate (800 mg, 3.4 mmol) in tetrahydrofuran (10 mL) was added 1 N aqueous lithium hydroxide (7 mL, 7 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the residue was diluted with water and acidified with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (648 mg, 92%) as a white powder. +ESI (M+H) 208.1; 1H NMR (400 MHz, DMSO-d6, δ): 13.43 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.44-8.45 (m, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.07-8.11 (m, 1H), 7.70 (d, J=8.5 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]([OH:22])([C:18]([F:21])([F:19])[F:20])[CH2:6][NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16]
Reactant: [N-]=[N+]=NCC(O)(CNC(=O)c1c(Cl)cccc1Cl)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC(O)(CNC(=O)c1c(Cl)cccc1Cl)C(F)(F)F
Reaction time: 24 h
Yield: 1509.9 %

Procedure:
A stirred solution of N-[2-(azidomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-2,6-dichlorobenzamide (0.06 g) in dry tetrahydrofuran (30 ml) was treated with polymer bound triphenylphosphine (3 mmol/g, 2.01 g). The mixture was vigorously stirred at room temperature for 19 hours before water (3 ml) was added. Stirring was continued at room temperature for a further 24 hours. The suspension was then diluted with tetrahydrofuran (50 ml) and then filtered through a pad of hyflo. The pad was washed with further tetrahydrofuran (2×30 ml). The combined filtrate and washings were partitioned between ethyl acetate (100 ml) and water (50 ml). The separated organic phase was further washed with water (2×50 ml), passed through a hydrophobic frit and concentrated in vacuo and then re-evaporated in vacuo with ethanol (1×20 ml) to give the title compound (0.84 g) as a near colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13]N1C=C(C)N=C1CC1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:4][CH:3]=1
Reactant: Cc1cn(CCCN)c(Cc2ccccc2)n1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NCCCCc1ccc(Cl)cc1

Procedure:
In a similar manner to Example 35, a mixture of 4-chlorobenzaldehyde (5.6 g) and 1-(3-aminopropyl)-2-benzyl-4-methylimidazole (9.2 g) in ethanol (100 ml) was stirred and then reduced with sodium borohydride (1.6 g) to give 3-(2-benzyl-4-methylimidazol-1-yl)-[-(4-chlorobenzyl)propylamine, b.p. 190°-200° C. (0.04 mmHg). Glc and 1H nmr indicated that the product contained 21% of 3-(2-benzyl-5-methylimidazol-1-yl)-N-(4-chlorobenzyl)propylamine.
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[CH2:16]([N:18]1[C:22]2=[N:23][CH:24]=[C:25]([C:34]([NH2:36])=O)[C:26]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:21]2[CH:20]=[N:19]1)[CH3:17]>C1COCC1>[CH2:16]([N:18]1[C:22]2=[N:23][CH:24]=[C:25]([C:34]#[N:36])[C:26]([NH:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[C:21]2[CH:20]=[N:19]1)[CH3:17]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(N)=O)cnc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCOCC3)c(C#N)cnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Burgess Reagent 4.53 g, 19.0 mmol) was added to a suspension of Intermediate 136 (5.0 g, 17.3 mmol) in THF (80 ml). The reaction mixture was stirred at room temperature for 18 hours then a further portion of Burgess Reagent (0.9 g, 1.8 mmol) was added and stirring continued for 5 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was washed with water, dried and evaporated in vacuo to afford Intermediate 137 as an off-white solid (4.43 g). LCMS showed MH+=272; TRET=2.40 min