Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:25])=[C:4]([C:8]([I:24])=[C:9]([NH:12][C:13](=[O:23])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(OC)(O[CH3:30])(=O)=O>>[NH2:1][C:2]1[C:3]([I:25])=[C:4]([C:8]([I:24])=[C:9]([N:12]([CH3:30])[C:13](=[O:23])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]=1[I:11])[C:5]([OH:7])=[O:6]
Reactant: COCCOCCOCC(=O)Nc1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: COS(=O)(=O)OC
Product: COCCOCCOCC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I

Procedure:
3-Amino-2,4,6-triiodo-5-(N-methyl-3,6,9-trioxadecanamido)benzoic Acid [C; Ro is H(CH2OCH2)3CON(CH3), Q is H, Z is OH] was prepared by methylation of 3-amino-2,4,6-triiodo-5-(3,6,9-trioxadecanamido)benzoic acid with dimethyl sulfate according to the procedure of Example 41, and was obtained as an amorphous pink solid, m.p. 100°-109° C. when recrystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14]CC)=[O:13].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl (4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained (98%) as a colorless solid: MS (ES−) m/z 415.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=2)[C:7]1=[O:19].[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([NH:31][CH2:30][CH2:29][NH+:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:18])[CH:12]=2)[C:7]1=[O:19]
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Product: O=C(NCC[NH+]1CCCCC1)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Product: [Cl-]

Procedure:
2-(3-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 2-piperidin-1-yl-ethylamine (113 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 135 mg (92%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([OH:45])=O)=[C:18]3[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:49]=C=NCCCN(C)C)C.C(N(CC)CC)C.N>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([NH2:49])=[O:45])=[C:18]3[N:17]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1ccc(C(=O)N(OC(C)(C)C)c2c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c(C(=O)O)cnn23)cc1
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)N(OC(C)(C)C)c2c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c(C(N)=O)cnn23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.25 g) in N,N-dimethylformamide (20 mL) were added ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g), N-hydoroxybenzotriazole monohydrate (0.31 g), triethylamine (2.8 mL) and ammonia (5.0 mL, 2.0 mol/L in methanol). The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH2Cl2, the combined organic layer was washed with water, dried over MgSO4, and the solvent was removed in vacuo to give the crude title compound (1.25 g) as a white solid. This crude product was used in the next reaction without further purification. ESI/MS data for this compound are shown below.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([C@H](C3C=CC=CC=3)C)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>[Pd].C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([NH:13][CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN([C@@H](C)Cc1ccc2c(c1)CCO2)[C@@H](C)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Yield: 92.2 %

Procedure:
A mixture of (S,S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-phenylethyl)amine (23 grams, 0.074 mole) and ammonium formate (30 grams, 0.48 mole) and 10% palladium on carbon (3.7 grams) in ethanol (300 ml) was heated under reflux for 2 hours. The mixture was filtered and the solvent was evaporated to give a residue which was partitioned between 5% sodium hydroxide and ether. Evaporation of the organic phase gave (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamine as an oil (14 grams, 92%), M+ 205.
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:19]1[CH2:24][CH2:23][N:22]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:20]1)=O)C1C=CC=CC=1.[BrH:35].C(O)(=O)C>>[BrH:35].[N:22]1([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:20][NH:19][CH2:24][CH2:23]1
Reactant: O=C(NN1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: O=C(NN1CCNCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 25% hydrogen bromide-acetic acid (30 ml) and anisole (1.6 ml) was added N-(4-benzyloxycarbonyl-1-piperazinyl)-p-fluorobenzamide (10 g) dropwise for 15 minutes under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 hours. The resulting precipitate was collected and washed with diethyl ether (10 ml) to give N-piperazinyl-p-fluorobenzamide hydrobromide (10.2 g) as white hydroscopic solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH:25]1[C:29]2[CH2:30][NH:31][CH2:32][CH2:33][C:28]=2[C:27]([OH:34])=[N:26]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.O>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([N:31]3[CH2:32][CH2:33][C:28]5[C:27]([OH:34])=[N:26][NH:25][C:29]=5[CH2:30]3)=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: Oc1n[nH]c2c1CCNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCc4c(O)n[nH]c4C3)nncc2c1
Temperature: 160 °C

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (300 mg, 888 μmol), 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ol (247 mg, 1776 μmol) and N,N-diisopropylethylamine (310 μl, 1776 μmol) in NMP (3 mL) was heated to 160° C. for 18 h. After cooling to RT, the mixture was diluted with H2O and extracted with 25% i-PrOH/CHCl3 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mM, 20 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to obtain the title compound. MS (ESI, pos. ion) m/z: 441 (M+1).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(OC(F)F)c([N+](=O)[O-])c1

Procedure:
10 4-Difluoromethoxybenzaldehyde (1.7 g, 10 mmol) was dissolved in concentrated sulfuric acid (8 mL) at 0 ° C. followed by dropwise addition of 70 % nitric acid (1,1 mL).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]=[N+:10]=[N-:11])=[C:6]([F:12])[CH:5]=[CH:4][CH:3]=1.[C:13]([C:16]([OH:18])=[O:17])#[C:14]C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[N:11]=[N:10]2)=[C:6]([F:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CC#CC(=O)O
Reactant: [N-]=[N+]=NCc1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(Cc2c(F)cccc2Cl)nn1

Procedure:
27.5 g (0.15 mole) of 6-chloro-2-fluorobenzyl azide and 10.5 g (0.15 mole) of propinecarboxylic acid in 300 ml of toluene are heated for 3 hours to 90° C. After cooling, the crystals are filtered with suction and recrystallised from acetonitrile to give 1-(6-chloro-2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 182° C. (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32]>>[CH3:26][C:23]1[C:22]([CH2:27][CH2:28][O:29][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CC(Br)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and (1-bromoethyl)benzene.
Reaction SMILES: [CH:1]([C@H:14]1[N:23]2[C@@H:18]([CH2:19][O:20][CH2:21][CH2:22]2)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]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.[ClH:31]>O1CCOCC1>[ClH:31].[ClH:31].[CH:1]([C@H:14]1[N:23]2[C@@H:18]([CH2:19][O:20][CH2:21][CH2:22]2)[CH2:17][NH:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2COCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(C(c2ccccc2)[C@@H]2CNC[C@@H]3COCCN32)cc1

Procedure:
(6R,9aR)-6-Benzhydryl-8-(tert-butoxycarbonyl)octahydropyrazino[2,1-c][1,4]oxazine was treated with 4N hydrogen chloride in 1,4-dioxane to give (6R,9aR)-octahydro-6-benzhydrylpyrazino[2,1-c][1,4]oxazine dihydrochloride as a yellowish powder. (6R,9aR)-6-Benzhydryl-8-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride was obtained from (6R,9aR)-6-benzhydrylhexahydropyrazino[2,1-c][1,4]oxazine dihydrochloride according to a similar manner to that of Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C(N(C(C)C)C(C)C)C>C1COCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=3)[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1ccc(N)cc1OCc1ccccc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 53.6 %

Procedure:
N-(4-Amino-2-benzyloxy-phenyl)-acetamide (419) (3 g, 11.72 mmol) and Fmoc-Cl (3.1 g, 12 mmol) were combined and dissolved in THF (60 mL). iPr2EtN (18 mmol, 1.2 equiv.) was added and the mixture was heated to 80° C. for 15 minutes while stirring. TLC indicated complete reaction at this point. The mixture was poured into ice-water (500 mL) and a white solid precipitated. The solid was collected by filtration under reduced pressure followed by drying under high vacuum to give the desired product (420) as a white powder (3 g, 6.28 mmol, 54% yield). LC-MS (ESI): (exact mass: 478.19) m/e=479.2 [M+1]+ (70%), 957.6 [2M+1]+ (100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:26]([CH:27]4[CH2:29][CH2:28]4)[N:25]=[N:24][N:23]=3)[CH:17]=1)[CH2:10][C:9]2([CH3:31])[CH3:30])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH:27]1([N:26]2[C:22]([C:18]3[CH:17]=[C:16]([CH:11]4[CH2:10][C:9]([CH3:30])([CH3:31])[C:8]5[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=5)[NH:12]4)[CH:21]=[CH:20][CH:19]=3)=[N:23][N:24]=[N:25]2)[CH2:28][CH2:29]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3nnnn3C3CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (908.0 mg, 2.2 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (100 mL×2), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (770.2 mg, 90%) as a off-yellow solid: MS (ESI) M+1=390.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH2:31][Cl:30])=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc(OCCCCCCCCCCN)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCCCCCCCCCNC(=O)CCl)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
The crude product from (iii) above (5.62 g, 18.84 mmol) and triethylamine (2.6 mL, 18.7 mmol) were dissolved in chloroform (90 mL) and cooled in an ice bath. A solution of chloroacetyl chloride (1.5 mL) in chloroform (40 mL) was added dropwise with stirring. After the completion of the addition, the solution was stirred in the ice bath for 15 minutes and warmed to ambient temperature and stirred for 20 hours. The solution was washed with water (4×80 mL). Drying (MgSO4) and concentration yielded the product (6.71 g, 93%) which was used without further purification. 1H NMR (CDCl3, δ): 7.95 (d), 6.87 (d), 6.54 s, br), 4.01 (d), 3.96 (t), 3.86 (s), 3.28 (q), 1.76 (m), 1.55 (m), 1.45 (m), 1.29 (m). 13C NMR (CDCl3, δ): 130.71, 130.66, 121.52, 113.23, 75.37, 67.33, 50.95, 41.85, 39.04, 28.56, 28.53, 28.47, 28.43, 28.33, 28.25, 25.94, 25.11.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5](C2CCCCO2)[CH2:4][N:3]1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([OH:21])C>>[OH:21][CH:5]1[CH2:4][N:3]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2](=[O:1])[CH2:6]1
Reactant: CCOC(=O)CN1CC(C2CCCCO2)CC1=O
Reactant: CCO
Product: CCOC(=O)CN1CC(O)CC1=O
Yield: 62 %

Procedure:
A solution of 0.16 g ethyl 2-oxo-4-(tetrahydropyran-2-yl)-1-pyrrolidineacetate is dissolved in 5 ml ethanol containing 16 mg pyridinium p-toluenesulphonate. The mixture is heated 4 h at 35° , the ethanol is evaporated and the residue chromatographed on silica. The title compound is obtained as a colourless oil in 62% yield.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C=CCCCCCCCCCCCCCCCCCCCCC
Agent: Cl
Product: CCCCCCCC/C=C\CCCCCCCCCCCCC

Procedure:
Crude tricosene made by the process described in Example I was treated two different ways and distilled under vacuum in order to determine whether isomerization had occurred. The first treatment involved washing with equal volumes of water, and then drying over MgSO4 prior to distillation. This resulted in 30.7% cis and 43.4% trans. In the second treatment, 6.5 l of 4M HCl was added followed by phase separation. The organic phase was then washed with 3 l of saturated sodium bicarbonate solution prior to distillation. This treatment resulted in 39.0% cis and 35.2% trans determined by GC as described above.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12][CH:13]=[CH:14][C:4]=2[N:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[CH3:1][CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12][CH:13]=[CH:14][C:4]=2[NH:3]1
Reactant: Cc1nc2ccsc2c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC1Nc2ccsc2-c2ccccc21
Temperature: 23 °C
Yield: 132.5 %

Procedure:
5-Methylthieno[3,2-c]isoquinoline (12 g, 60 mmol) and sodium borohydride (9.0 g, 240 mmol) were combined in dry 1,4-dioxane (200 mL) at 23° C. Trifluoroacetic acid (9.2 mL, 120 mmol) was slowly added via syringe with gentle bubbling. After the addition was complete, the mixture was heated to reflux for 24 h. At this time the mixture was cooled to 23° C., quenched with de-gassed saturated aqueous sodium bicarbonate (450 mL) and extracted under nitrogen with de-gassed methylene chloride (3×ca. 150 mL). The combined extracts were washed under nitrogen with de-gassed brine (ca. 450 mL), dried (Na2SO4) under nitrogen and concentrated in vacuo to give the crude title compound (16 g) as an air-sensitive orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH:4]([C:3]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:2]=1[O:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C)cc1C=O
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
To a solution of 2-hydroxy-5-methylbenzaldehyde (2 g, 14.69 mmol) in 22 mL of DMF was added K2CO3 (4.06 g, 29.4 mmol) under N2 at room temperature. After the mixture was stirred for 10 min, ethyl 2-bromoacetate (1.625 mL, 14.69 mmol) was added. The reaction mixture was stirred at room temperature overnight, and filtered through Celite to remove solids. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash chromatography, 100% Heptane-20% Ethyl Acetate/80% Heptane, to give a white solid, ethyl 2-(2-formyl-4-methylphenoxy)acetate (2.5 g). LCMS retention time=1.19 minutes (LC method 3); MS (m+1)=222.9. 1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3H), 2.28 (s, 3H), 4.17 (q, J=7.2 Hz, 2H), 4.95 (s, 2H), 7.08 (d, J=8.6 Hz, 1H), 7.45 (ddd, J=8.6, 2.5, 0.6 Hz, 1H), 7.51 (d, J=2.2 Hz, 1H), 10.41 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][C@H:16]([C:18]([OH:20])=[O:19])[NH2:17].[CH3:21]O>>[CH3:21][O:19][C:18](=[O:20])[C@@H:16]([CH2:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)[NH2:17]
Reactant: N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)Cc1ccc2ccccc2c1
Temperature: 60 °C

Procedure:
Thionyl chloride (5 ml) was added dropwise over 15 min. to a suspension of (R)-3-(2-naphthyl)alanine (5.0 g) in methanol (50 ml) at 35° C. After addition the mixture was heated at 60° C. for 1 h, cooled and the solvent removed in vacuo. Water (75 ml) and ethyl acetate (125 ml) were added and pH was adjusted to 8.5 with sodium carbonate. The organic phase was separated and dried (magnesium sulfate) to afford 4.86 g of (R)-3-(2-naphthyl)alanine methyl ester.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15](OC)(=O)[C:16]([O:18][CH3:19])=[O:17].C[O-].[Na+].C(O)(=O)C>CN(C)C=O>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:11](=[O:12])[CH:13]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[O:10][C:9]=2[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: COC(=O)C(=O)OC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a solution of 99.7 g (0.513 mole) of 2,4-dihydroxy-3-propylacetophenone and 72.7 g (0.77 mole) of dimethyl oxalate in 1 liter of dry dimethylformamide was added in portions 97 g (1.8 mmole) of sodium methoxide. After stirring for 4 hours, 1.8 l of acetic acid was added and stirring was continued for 4 days. The reaction mixture was heated in a steam bath for four hours and evaporated to dryness. Water was added to the residue and the mixture was heated to boiling. A solid was filtered off and recrystallized from ethanol to give 89.8 g of the title compound, mp. 222°-224°. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][O:20]1.[CH3:26][NH:27][CH3:28]>O1CCCC1>[CH3:26][N:27]([CH3:28])[CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: c1ccc(OCC2CO2)c(CCCCc2ccc3ccccc3c2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccc2ccccc2c1
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 1(b), 291 mg of 2-{2-[4-(2-naphthyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 5 ml of tetrahydrofuran were treated with 1 ml of 50% by volume aqueous dimethylamine. The crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 279 mg (yield 84%) of the title compound.