Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33]1([CH2:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:33]1([CH2:39][NH:40][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCC1CCCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCC2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.017 (0.23 mmole) of cyclohexanemethanamine, 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water (gradient, 20:80-100:0) to give 0.012 g of N-cyclohexylmethyl-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-32) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[N:10]([CH3:31])[C:11](=[O:30])[C:12]([C:21]2[CH:22]=[C:23]([CH:28]=[O:29])[N:24]([CH2:26][CH3:27])[CH:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[N:13]=1.[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(O)C>[NH2:8][C:9]1[N:10]([CH3:31])[C:11](=[O:30])[C:12]([C:21]2[CH:22]=[C:23]([CH:28]=[O:29])[N:24]([CH2:26][CH3:27])[CH:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:38]3[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=3)[CH:15]=2)[N:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: CCn1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)cc1C=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Yield: 74 %

Procedure:
A 1:1 mixture of toluene and ethanol was sparged with nitrogen for 30 minutes. To the solvent was added 4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-1-ethyl-1H-pyrrole-2-carbaldehyde (1.10 g; 3.04 mmol), 2-fluoro-3-pyridineboronic acid (0.69 g; 4.9 mmol), sodium carbonate (1.03 g; 9.75 mmol), and tetrakis[triphenylphosphine]-palladium(0) (0.53 g; 0.46 mmol). This mixture was heated at reflux temperature for three hours. The solvents were evaporated and the residue was crystallized in CHCl3 and water to give the title as grey crystals, 0.91 g (74% yield),
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[O:34][CH:33]=[CH:32][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)[N:20]=2)[CH2:11][CH2:10]1)(C)(C)C.ClC1N=C(Cl)C2OC=CC=2N=1.C(OC(NCC1CCNCC1)=O)(C)(C)C.NC1C=CC(S(N)(=O)=O)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[O:34][CH:33]=[CH:32][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:29])(=[O:31])=[O:30])=[CH:26][CH:27]=3)[N:20]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Nc3ccc(S(N)(=O)=O)cc3)nc3ccoc23)CC1
Agent: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: Clc1nc(Cl)c2occc2n1
Agent: Nc1ccc(S(N)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(c2nc(Nc3ccc(S(N)(=O)=O)cc3)nc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a flask containing tert-butyl(1-(2-(4-sulfamoylphenylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.215 g, 0.428 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] with 4-(tert-butoxycarbonylaminomethyl)piperidine [Tyger] and B with 4-aminobenzenesulfonamide) was slowly added a 20% TFA/DCM (3 mL) solution. The mixture was stirred at rt for about 4 h. The solvent was removed in vacuo and the residue purified by reverse phase preparatory HPLC (Table 2, method b) to provide 4-(4-(4-(aminomethyl)piperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)benzenesulfonamide (0.142 g, 63%): LC/MS (Table 2, Method a) Rt=0.20 min; MS m/z 403.2 (M+H)+. Syk IC50=A
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g., 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.265 g., 1 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform-hexane (20:80) as eluant to give 2k; yield: 0.25 g. (54.2%), m.p. 151° C., C24H20ClF3N2O2; 1H NMR δ ppm (CDCl3): 2.00 (bs, 2H), 2.79 (t, 2H), 3.36 (t, 2H), 4.46 (s, 2H), 6.42-6.46 (m, 1H), 6.70-6.79 (m, 2H), 6.96 (s, 1H), 7.23-7.31 (m, 5H), 7.75-7.82 (m, 2H); IR vmax (KBr) (cm−1): 555, 701, 898, 1027, 1218, 1362, 1509, 1635, 1721, 2375, 2658, 2957, 3028, 3449, 3756; MS: m/z=461 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].ICC>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC#N
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.17 g, 0.85 mmol), acetonitrile (4 mL), sodium carbonate (0.11 g, 2.12 mmol) and iodoethane (0.13 g, 0.85 mmol) was stirred at ambient temperature for 72 h. Water (30 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.11 g). [α]D=−21.4° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 111-112° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:39]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:40]=[CH2:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[N:14]=[C:13]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32]([NH:45][S:42]([CH2:39][CH:40]=[CH2:41])(=[O:44])=[O:43])=[O:33])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: C=CCS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)NS(=O)(=O)CC=C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 2-(4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetic acid (50 mg, 0.09 mmol) in DMF (2 mL) was added prop-2-ene-1-sulfonamide (17 mg, 0.14 mmol), HATU (71 mg, 0.19 mol) and iPr2NEt (66 uL, 0.38 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed nuder vacuum and the residue was purified by silica gel column (MeOH/DCM=5% to 10%) to give 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2-(allylsulfonamido)-2-oxoethyl)benzamide (53 mg, 89%) as a white solid.
Reaction SMILES: CSCCO.[H-].[Na+].[N+:8]([C:11](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:12]([O:14]C)=[O:13])([O-:10])=[O:9]>CN(C)C=O>[N+:8]([C:11](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:12]([OH:14])=[O:13])([O-:10])=[O:9]
Reactant: COC(=O)C(=C1NCCCO1)[N+](=O)[O-]
Agent: CSCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(=C1NCCCO1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g Of 2-(methylthio)ethanol was added dropwise over a 30-minute period to a stirred mixture of 3.0 g of 57% mineral oil dispersion of sodium hydride in 50 ml of dry dimethylformamide at 0°. The mixture was allowed to warm to room temperature and stirred for 1 hour. Then 6.1 g of 1A was added all at once and the mixture was stirred at room temperature overnight and extracted with ether and with methylene chloride. the aqueous layer was acidified and extracted with methylene chloride. The latter extract was washed with water, dried (MgSO4), decolorized and filtered and the solvent was evaporated under reduced pressure. The residue was crystallized from pentane, then recrystallized from ethyl acetate-ether to give the 2-(methylthio)ethyl ester of nitro(tetrahydro-2H-1,3-oxazin-2-ylidene)acetic acid (1B) as a pale yellow solid, m.p.: 88.5°-89.5°.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:25][O:26][CH2:27][CH3:28])[N:21]([CH2:22][CH2:23][CH3:24])[C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:27]([O:26][CH2:25][C:20]1[N:21]([CH2:22][CH2:23][CH3:24])[C:12]2[C:11]3[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:19]=1)[CH3:28]
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCc4ccccc4)cc3c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Reaction time: 3 h
Yield: 94.1 %

Procedure:
8-Benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinoline (15.00 g, 39.84 mmol) and ethanol (300 mL) were added to a Parr vessel. A mixture of palladium hydroxide (2.0 g, 20% on carbon) in ethanol (100 mL) was then added. The vessel was purged with nitrogen, placed under hydrogen pressure (25 psi, 1.7×105), and shaken for three hours. The vessel was then refilled with hydrogen (25 psi, 1.7×105) and shaken for 18 hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol (2 L). The filtrate was concentrated under reduced pressure, and the resulting orange oil was dissolved in toluene and concentrated under reduced pressure to provide 10.7 g of 2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol as a granular, orange solid.
Reaction SMILES: C(OC1C=CC(OC2C=CC(C(C)(C)C)=CC=2)=C([N+]([O-])=O)C=1)C1C=CC=CC=1.C([O-])=O.[K+].[NH2:33][C:34]1[C:35]([O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=2)=[CH:36][CH:37]=[C:38]([OH:40])[CH:39]=1.[C:52]([C:57]1[CH:71]=[C:70]([C:72]([CH2:75][CH3:76])([CH3:74])[CH3:73])[CH:69]=[CH:68][C:58]=1[O:59][CH:60]([CH2:64][CH2:65][CH2:66][CH3:67])[C:61](Cl)=[O:62])([CH2:55][CH3:56])([CH3:54])[CH3:53]>O.C1(C)C=CC=CC=1.[Pd].C(O)(C)C>[C:48]([C:45]1[CH:46]=[CH:47][C:42]([O:41][C:35]2[C:34]([NH:33][C:61](=[O:62])[CH:60]([O:59][C:58]3[CH:68]=[CH:69][C:70]([C:72]([CH2:75][CH3:76])([CH3:73])[CH3:74])=[CH:71][C:57]=3[C:52]([CH2:55][CH3:56])([CH3:54])[CH3:53])[CH2:64][CH2:65][CH2:66][CH3:67])=[CH:39][C:38]([OH:40])=[CH:37][CH:36]=2)=[CH:43][CH:44]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)c1ccc(Oc2ccc(O)cc2N)cc1
Reactant: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Agent: [Pd]
Agent: CC(C)(C)c1ccc(Oc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Agent: O=C[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)ccc1Oc1ccc(C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
In a 500-ml flask, place 18.9 g (0.05 m) of 5-benzyloxy-2-(4-t-butyl-phenoxy)-nitrobenzene (3a), 80 ml of isopropyl alcohol and 40 ml of toluene. Heat the mixture to 60° C. Add 1.0 g of 5% Pd/C wet with 1 ml of water and 21.0 g (0.25 m) of potassium formate in 30 ml of water. Stir the reaction mixture vigorously at 60°-70° C. for 3 hrs under nitrogen. Cool the reaction mixture containing 5-amino-4-(4-t-butylphenoxy)phenol (4a, Y=4-t-butylphenoxy) to 15° C. and add 20.3 g (0.05 m×1.05 @95%) of 2-(2,4-di-t-pentylphenoxy)hexanoyl chloride (R′COZ; R′=1-(2,4-di-t-pentylphenoxy)pentyl and Z=Cl) in 80 ml of toluene slowly over 10 min. Stir the mixture at room temperature for another 30 min and add 100 ml of water. Filter off catalyst and wash with a small volume of toluene and water. Separate toluene solution, wash with 200 ml of 1N HCl twice, and concentrate under a reduced pressure to a thick oil. Add 200 ml of heptane to the oil with gentle stirring. Cool in an ice-water bath for 1 hr. Collect solid, wash with heptane, and dry in a vacuum oven to give 27.0 g (92%) of 4-(4-t-butylphenoxy)-5-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-phenol (5a; Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:22][C@@H:23]([CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH3:22][C@@H:23]([CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][N:13]=2)=[CH:16][CH:17]=1
Reactant: CC[C@H](C)CCCCCBr
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCc1ccc(-c2ccc(OCCCCC[C@@H](C)CC)cc2)nc1
Temperature: -25 °C
Yield: 23.8 %

Procedure:
A mixture of 0.355 g of crude p-(5-octyl-2-pyridyl)-phenol, 10 ml of ethanol, 0.260 g of (S)-6-methyloctyl bromide, 0.172 g of potassium carbonate and a spatula tip of sodium iodide was heated to 90° C. (oil bath temperature) for about 60 hours while stirring. The brown suspension obtained was subsequently cooled and concentrated in a vacuum. The brown oily residue was separated by chromatography on 120 g of silica gel at 0.4 bar with methylene chloride/acetone (vol. 99:1). The resulting brownish paste (0.367 g) was dissolved in about 5 ml of hexane, the solution was filtered and the filtrate was cooled to -25° C. The precipitate was filtered off under suction and distilled at 250° C/0.05 bar, there being obtained 0.122 g of (S)-2-[p-(6-methyloctyloxy)phenyl]-5-octylpyridine as a light yellowish smectic liquid crystal. Concentration of the mother liquor and subsequent distillation gave a further 0.164 g of (S)-2-[p-(6-methyloctyloxy)phenyl]-5-octylpyridine as a light yellowish smectic liquid crystal. The product (total 0.286 g) was treated with diethyl ether, evaporated, dried at 80° C. for 2 hours and again distilled, there being obtained 0.245 g of (S)-2-[p-(6-methyloctyloxy)phenyl]-5-octylpyridine; m.p. (C-S) 36.1° C., phase transition (S--Sc*) 57° C., cl.p. (Sc* --I) 70.4° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C)C=O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
63.9 g of 5-chloro-2-nitrobenzonitrile was dissolved in 200 ml of dimethylformamide, and 95 ml of piperidine was added to the solution. The mixture was stirred at 50° C. for 30 minutes while externally cooling because of heat generation. The reaction mixture was poured into water, and the precipitate thus formed was collected, washed with water and then with methanol, and dried to obtain 80 g of 2-nitro-5-piperidinobenzonitrile (melting point: 126°-127° C.).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[C:23]([C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C#CCCCC
Reactant: CNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCCC#Cc1nc(N)c2nc(NC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-methylaminoadenosine (7, 50 mg, 0.12 mmol) and 1-hexyn (0.58 mmol). The mixture was purified by column chromatography (5% MeOH in CH2Cl2). Yield 36 mg (0.09 mmol, 79%), mp 161–163÷C; Rƒ 0.23 (5% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 7.01 (d, 1H, J=4.81 Hz, NH), 6.61 (s, 2H, NH2), 5.84 (d, 1H, J=7.55 Hz, H-1′), 5.78 (t, 1H, J=4.47 Hz, OH-2′), 5.26 (d, 1H, J=6.87 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.58 (q, 1H, J=5.83 Hz, H-2′), 4.10–4.03 (m, 1H, H-3′), 3.95 (bs, 1H, H-4′), 3.62 (bs, 2H, H-5′), 2.87 (s, 3H, J=4.46 Hz, NHCH3), 2.36 (t, 2H, J=6.87 Hz, ≡CCH2), 1.53–1.39 (m, 4H, CH2CH2), 0.89 (t, 3H, J=6.87 Hz, CH3); MS m/z 376 (M+H)+; Anal. (C17H24N6O4) C, H, N.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[NH4+:13].[OH-]>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH2:13])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.7 %

Procedure:
Isatoic anhydride (40 g, 245 mmol) was suspended in 650 mL 1 N NH4OH (2.5 equiv) and stirred at room temperature for 3 days. The precipitate was filtered and washed with water. The product was then dissolved in THF, filtered, and concentrated to dryness. The product was dried by azeotropic distillation with toluene and washed with CH2Cl2 to yield 10.9 g (32.7%) of 2-amino-benzamide.
Reaction SMILES: [O:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]>O1CCCC1>[O:1]1[C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccno1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccno1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 53.9 %

Procedure:
To a solution of isoxazole-5-amine (740 mg, 8.80 mmol) and pyridine (2.14 ml, 26.4 mmol) in tetrahydrofuran (10 ml) was added 2,2,2-trichloroethyl chloroformate (1.82 ml, 13.2 mmol) with ice-cooling and the mixture was stirred for 40 minutes with ice-cooling. To the mixture was further added 2,2,2-trichloroethyl chloroformate (1.82 ml, 13.2 mmol) with ice-cooling and the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (1.23 g, 53.9%) as a solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1Cl>>[O:23]=[C:21]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=1)[CH2:22][O:3][C:1](=[O:4])[CH3:2]
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1ccccc1
Yield: 33 %

Procedure:
This crude material was reacted with acetic acid (1.42 mL, 1.49 g, 24.8 mmol) and triethylamine (3.46 mL, 2.51 g, 24.8 mmol), as described above for the synthesis of 3-(3,4-dichlorophenyl)propan-2-one. Flash chromatography over silica gel (10-30% ethyl acetate in hexanes) gave pure product (0.83 g, 33% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.08 (s, 3H) 3.80 (s, 2H) 4.85 (s, 2H) 7.17-7.36 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]3[NH:34][N:33]=[N:32][N:2]=3)[O:4][C:5]=2[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nc2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCc2ccc3nc(-c4nnn[nH]4)oc3c2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A solution-suspension of 2-cyano-6-[3-(2-quinolinylmethyloxy)phenoxymethyl]benzoxazole (660 mg, 1.62 mmol), sodium azide (316.3 mg, 4.86 mmol) and ammonium chloride (260.2 mg, 4.86 mmol) in DMF (11 ml) is heated to 110° C. for 5 hours and stirred at room temperature for 12 hours. The mixture is poured over ice-water and the pH adjusted to 10 with 1N NaOH. The aqueous mixture is washed with ether and the pH adjusted to 4 with 1N HCl. The precipitated solid is filtered and washed successively with water, ethanol and methylene chloride. Recrystallization from ethanol-DMF affords 5-(6-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoxazol-2-yl)tetrazole (M.P. 223-225° C. dec.).