Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]1[S:28][CH:29]=[C:30]([C:32]([OH:34])=[O:33])[N:31]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39](O)([CH3:41])[CH3:40].C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]1[S:28][CH:29]=[C:30]([C:32]([O:34][CH:39]([CH3:41])[CH3:40])=[O:33])[N:31]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)O
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nc(C(=O)O)cs4)cc23)cc1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nc(C(=O)OC(C)C)cs4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a mixture of 2-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]-1,3-thiazole-4-carboxylic acid (0.26 g, 0.5 mmol), n-tributylphosphine (0.25 ml, 1.0 mmol), isopropanol (0.5 ml) and tetrahydrofuran (10 ml) was added 1,1-(azodicarbonyl)dipiperidine (0.25 g, 1.0 mmol), and the mixture was stirred at room temperature for 2 hrs. Precipitated crystals were removed and the solvent was evaporated. The residue was purified by silica gel column chromatography to give isopropyl 2-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]-1,3-thiazole-4-carboxylate (0.20 g, yield 71%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]3[N:15]([CH3:16])[N:14]=[C:13]([C:17]([NH:19][C:20]4[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:28][CH3:29])=[O:18])[C:9]=3[CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][N:3]=1.I[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][C:32]=1[O:44][CH3:45].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:26]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:28][CH3:29])[C:20]=1[NH:19][C:17]([C:13]1[C:9]2[CH2:10][CH2:11][CH2:12][C:5]3[C:6](=[N:7][C:2]([NH:1][C:31]4[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])=[CH:33][C:32]=4[O:44][CH3:45])=[N:3][CH:4]=3)[C:8]=2[N:15]([CH3:16])[N:14]=1)=[O:18])[CH3:27]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(N)nc1-2
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)OC(C)(C)C)cc3OC)nc1-2
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of 9-amino-N-(2,6-diethylphenyl)-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxamide (0.375 mg, 0.96 mmol) in dioxane (10 mL), tert-butyl 4-iodo-3-methoxybenzoate (0.320 mg, 0.96 mmol) and Cs2CO3 (0.470 g, 1.44 mmol) were added and the flask was evacuated and backfilled with argon. Pd2(dba)3 (0.088 g, 0.096 mmol) and Xantphos (0.110 g, 0.192 mmol) were then charged and the mixture was refluxed under argon for 4 h. After cooling to room temperature, the reaction mixture was concentrated, suspended in water (50 mL) and extracted with AcOEt. The organic phase was anidrified on Na2SO4, filtered and evaporated to dryness, the crude solid was purified by flash chromatography on silica gel (eluant: hexane/AcOEt 8/2) to afford 0.480 g (84% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][O:29]C3CCCCO3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCOC2CCCCO2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
Dissolve 4-{4-(3-chloro-4-fluoro-phenyl)-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (6.85 g; 13.48 mmol) in THF (200 mL) and add 1M aqueous hydrogen chloride (20 mL) and stir 18 h at RT. Dilute with EA, wash with saturated sodium bicarbonate, brine, dry with anhydrous MgSO4, filter, and evaporate. Purify the residue on 330 g silica gel with 2:1 DCM/EA to provide the title compound (5.07 g; 89%) as a white crystalline solid. MS (ES): m/z=424 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([N:23]([CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:47]([NH2:50])[CH2:48][NH2:49]>>[NH2:49][CH2:48][CH2:47][NH:50][C:2]1[N:3]=[C:4]([N:23]([CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:36])([CH3:37])[CH2:29]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:5]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:21])([CH3:22])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:7]=1
Reactant: NCCN
Reactant: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCN(c1nc(NCCN)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 0.5 h

Procedure:
53.6 g of 2-chloro-4,6-bis-(2,2,6,6-tetramethyl-4-piperidyl-butylamino)-1,3,5-triazine in 200 ml of ethylenediamine are refluxed for 24 hours. 200 ml of toluene and 100 ml of 30% sodium hydroxide solution are added to the reaction mixture and the resulting mixture is stirred vigorously for 30 minutes. The aqueous solution is separated off and the toluene solution is washed with twice 200 ml of water, dried over sodium sulfate and evaporated. The 2-(2-aminoethylamino)-4,6-bis-(2,2,6,6-tetramethyl-4-piperidyl-butylamino)-1,3,5-triazine thus obtained is dissolved in 200 ml of xylene and the resulting solution is cooled to 5°. 6.1 g of cyanuric chloride are introduced at this temperature and the reaction mixture is stirred at 5°-10° for 1 hour. After adding 1.4 g of finely powdered sodium hydroxide, the temperature is raised to 35°-40° and the mixture is stirred for 2 hours at this temperature. After adding a fresh portion of 1.4 g of sodium hydroxide, the mixture is heated slowly to the reflux temperature. After refluxing for 3 hours, a final portion of 1.4 g of sodium hydroxide is added and the reaction mixture is then stirred under reflux for 18 hours. After cooling, 200 ml of water are added, the mixture is stirred well for 10 minutes, the aqueous solution is separated off and the xylene solution is washed with 3 times 100 ml of water. The xylene solution is evaporated in vacuo and the residue is then dried under a high vacuum (130°/0.001 mm Hg). The resulting glassy, yellowish mass can be comminuted to a virtually colourless powder. The light stabiliser having the above structural formula melts at about 140°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>CC#N>[CH:27]1([NH:26][C:24](=[O:25])[CH2:23][N:8]2[C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[S:4][C:5]=3[N:6]=[CH:7]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Reactant: O=C(CCl)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2ncn(CC(=O)NC3CCCCC3)c(=O)c2c1C

Procedure:
To a suspension of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (2.24 g, 10 mmol) in CH3CN (25 mL) was added K2CO3 (1.38 g, 10 mmol), KI (1.61 g, 10 mmol), and 2-chloro-N-cyclohexylacetamide (1.75 g, 10 mmol). The reaction mixture was refluxed overnight and quenched with H2O (120 mL). The resulting precipitate was filtered and dried to afford methyl 3-(2-(cyclohexylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, as a solid (yield: quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:23][CH3:24])[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH:26]([CH3:41])[CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:5]1[C:4]([O:23][CH3:24])=[CH:3][C:2]([NH:1][CH:26]([CH3:41])[CH2:27][CH2:28][CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: CCCCCCCCCCOc1c(OC)cc(N)c2ncccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1c(OC)cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2ncccc12
Yield: 49.8 %

Procedure:
A stirred mixture of 3.65 g of 8-amino-5-decoxy-6-methoxyquinoline and 3.5 g of 4-bromo-1-phthalimidopentane was maintained at 140°-145° while 1 g of triethylamine was added in portions during 1.5 hr. Five more increments of 4-bromo-1-phthalimidopentane (3 g) and triethylamine (1 g) were added at 1.5 hr intervals in the usual manner. The mixture was allowed to cool and extracted with diethyl ether (ca. 300 ml). Treatment of the extract with diethyl ether-hydrochloric acid gave a red oil. The oil was dissolved in chloroform (200 ml) washed with dilute sodium hydroxide (2×30 ml) and water, dried (potassium carbonate) passed through a silica column and concentrated to give 3 g of phthalimide derivative as a red oil. This material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CC1CCCO1>[CH3:8][C:6]1[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: C1CCNCC1
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 53.7 %

Procedure:
To a solution of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)acetate (3 g; 10.32 mmol) in 2-methyltetrahydrofuran (20 ml) was added piperidine (4.09 mL; 41.3 mmol) and triethylamine (5.72 mL; 41.3 mmol). The reaction was heated under reflux for 5 h and the reaction mixture was partitioned between ethyl acetate and a saturated solution of sodium hydrogen carbonate. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 1.88 g (48%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:15]([OH:17])=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CC(N(C)C)=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:23][O:22][N:21]([CH3:20])[C:15]([C:5]1[C:4](=[O:18])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=1)=[O:17]
Reactant: CNOC
Reactant: COc1cn(-c2ccccc2)nc(C(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cn(-c2ccccc2)nc(C(=O)N(C)OC)c1=O
Temperature: 50 °C
Yield: 83.4 %

Procedure:
Under an argon atmosphere, 5-methoxy-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylic acid (40 g) was dissolved in dimethylacetamide (600 mL) by heating to 50° C., and ice-cooled. With stirring, N,O-dimethylhydroxylamine hydrochloride (23.7 g), 1-hydroxybenzotriazole (21.9 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.6 g) were added, and triethylamine (81.4 mL) was added, and the mixture was allowed to warm to room temperature and stirred for 96 hr. To the reaction mixture was added ethyl acetate, and an insoluble material was filtered off. The filtrate was concentrated under reduced pressure to dryness, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) to give the title compound (39.2 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].O>N1C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([C:4](=[O:5])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[NH2:21]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: NNc1ccccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: NN(C(=O)c1c(F)cccc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
71.7 g (0.37 mol) of 2-chloro-6-fluorobenzoyl chloride are slowly added dropwise to a solution, cooled to 5° C., of 65.4 g (0.37 mol) of o-trifluoromethylphenylhydrazine in 200 ml of pyridine in such a manner that the temperature of the reaction mixture does not exceed 5° C. The mixture is stirred at room temperature for a further 90 minutes and subsequently treated with 400 ml of water. The aqueous phase is extracted three times with 150 ml of diethyl ether each time and the combined organic phases are washed in sequence with 2N sodium hydroxide solution and concentrated sodium chloride solution. The organic phase is then dried over anhydrous sodium sulfate and evaporated under reduced pressure, the crude product being evaporated twice with a small amount of toluene in order to remove excess pyridine. After recrystallization from methylene chloride/n-hexane there is obtained N1 -(α,α,α-trifluoro-o-tolyl)-2-chloro-6-fluorobenzhydrazide, m.p. 147°-148° C.; mass spectrum: 332(19), 157(100).
Reaction SMILES: [ClH:1].[CH2:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH2:7][CH2:6]1)[CH2:3][CH3:4].C>C(O)C>[ClH:1].[CH2:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCN1CC=C(c2cccc3c2CC(=O)N3)CC1
Agent: Cl
Solvent: CCO
Product: CCCN1CCC(c2cccc3c2CC(=O)N3)CC1
Yield: 72.9 %

Procedure:
1.69 g of the hydrochloride of Example 22 were hydrogenated in 300 ml of ethanol in the presence of 0.8 g of 10% palladized charcoal and the mixture was filtered. The filtrate was evaporated to dryness and the product was crystallized from ethanol to obtain 1.24 g of 1,3-dihydro-4-(1-propyl-piperidin-4-yl)-2H-indol-2-one hydrochloride melting at 270°-275° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[Cl:11].[C-:12]#[N:13].[K+]>C(O)C.O>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH2:9][C:12]#[N:13])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Br)c(Cl)c1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(F)ccc(Br)c1Cl
Reaction time: 16 h
Yield: 100.2 %

Procedure:
A solution of 1-bromo-3-bromomethyl-2-chloro-4-fluorobenzene (9.945 g) in absolute ethanol (40 mL) was added dropwise to a solution of potassium cyanide (2.38 g) in water (2 ml) under heating over a period of 30 minutes. The reaction mixture was heated to reflux for 7 hours. The reaction mixture was then allowed to cool and stored at ambient temperature for 16 hours. The mixture was filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate, dried over magnesium sulfate and concentrated to give (3-bromo-2-chloro-6-fluoro-phenyl)-acetonitrile as a pale yellow oil (8.19 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8]/[N:9]=[CH:10]/[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(/C=N/CC(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CNCC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of Example D (8.5 g, 30 mmol) in MeOH (80 mL) was slowly added solid NaBH4 (3.42 g, 90 mmol) while the reaction temperature was controlled below 20° C. After stirring for 2 h, the reaction was quenched with H2O, extracted with EtOAc (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo. The residue was purified via flash column chromatography to yield methyl 4-(((t-butoxycarbonyl)methylamino)methyl)benzoate (6.55 g, 77% yield). 1H NMR (CDCl3) δ 7.98 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 3.90 (s, 3H,) 3.84 (s, 2H) 3.29 (s, 2H) 1.46 (s, 9H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:33])[CH2:10][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][OH:13]>C1COCC1>[CH3:8][N:9]([CH3:33])[CH2:10][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][O:13][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC(CO)CN(C)C
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(COC(=O)CCC(=O)O)CN(C)C

Procedure:
Succinic anhydride (0.60 g, 5.99 mmol, 1.1 equiv) was added in one portion to a dry THF (11 mL) solution of 3-(dimethylamino)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-ol (2.0 g, 5.45 mmol, 1.0 equiv) and the resultant was refluxed for 18 hours under argon. The mixture was concentrated and then dissolved in EtOAc (10 mL) and poured into deionized water (20 mL). The layers were separated and the aqueous layer was extracted with two additional portions of EtOAc (25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to provide crude 4-(3-(dimethylamino)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propoxy)-4-oxobutanoic acid, a thick yellow oil, which was used without further purification.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:14])=[N+:2]=[N-:3].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>O1CCCC1>[N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[O:14][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: [N-]=[N+]=N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a stirred solution of trans 3-azido-2-hydroxy-1,2,3,4-tetrahydronaphthalene (95 mg, 0.55 mmol) in tetrahydrofuran (5 mL) at 0° C. under nitrogen was added sodium hydride (60% oil dispersion, 26 mg, 0.66 mmol). Gas evolution was observed and the reaction mixture turned cloudy. After slowly warming up to room temperature for 20 min, t-butyl bromoacetate (0.12 mL, 0.83 mmol) was added. After 2 h, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum to yield a residue. The residue was purified by silica gel chromatography (7% ethyl acetate in hexane was used) to obtain the title compound (90 mg). 13C NMR (400 MHz, CDCl3) δ 169.59, 133.18, 132.59, 128.88, 128.45, 126.50, 126.37, 81.76, 78.89, 67.99, 61.40, 33.95, 33.51, 28.08. 1H NMR (400 MHz, CDCl3) δ 7.03-7.17 (m, 4H), 4.20 (s, 2H), 3.91 (m, 1H), 3.73 (m, 1H), 3.29 (dd, J=5.7, 16.8 Hz, 1H), 3.16 (dd, J=5.7, 16.8 Hz, 1H), 2.90 (dd, J=8.4, 17.0 Hz, 1H), 2.80 (dd, J=8.4, 17.0 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[CH:1]([C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C(=Cc1nc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 2-methylbenzothiazole (1.49 g, 0.01 mol), benzaldehyde (1.27 g, 0.012 mol), 50% sodium hydroxide solution (3 ml), toluene (5 ml) and compound 1 (1 mmol) was stirred at reflux temperature for 4 hours. The reaction mixture was allowed to cool to room temperature and then diluted with water (10 ml). The organic layer was separated and the aqueous phase extracted with toluene. The combined organic portions were dried over magnesium sulphate and evaporated to give a solid residue which was crystallized from ethanol to give the corresponding 2-styrylbenzothiazole.
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C.O.[Pd]>[ClH:1].[ClH:1].[CH3:23][N:22]([CH3:24])[C:19]1[CH:18]=[CH:17][C:16]([CH:13]2[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C2CCNCC2)cc1
Reaction time: 10 h
Yield: 86.7 %

Procedure:
1-Benzyl-4-(4-dimethylaminophenyl)-1,2,3,6-tetrahydropyridine dihydrochloride (3.65 g) prepared in Example 46 was dissolved in a solvent mixture of 20 ml of ethanol and 5 ml of water. Using 10% palladium-on-carbon as the catalyst, the mixture was subjected to catalytic reduction at atmospheric temperature and pressure for 10 hours. The catalyst was then filtered off and the solvent was distilled off. The residual oil was diluted with a saturated aqueous solution of sodium chloride, made basic by addition of solid sodium hydrogen carbonate and extracted with acetonitrile. The extract was dried and 5 ml of 2N-ethanolic hydrochloric acid was added. Finally the solvent was distilled off and the residue was recrystallized from ethanol to give 1.2 g of colorless crystals melting at 215°-220° C.
Reaction SMILES: [Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](O)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O.C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:14])[C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2sc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2sc(Br)cc12
Temperature: 80 °C
Yield: 83 %

Procedure:
To 6-bromothieno[2,3-d]pyrimidin-4-ol (3.0 g, 19.7 mmol) was added phosphorus oxychloride (5 mL). After heating to 80° C. for 1.5 hours, the reaction mixture was poured into saturated NaHCO3 and ice. The solid was filtered, washed with water and dried to provide the product (4.06 g, 83%) as brown solid.