Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CC=CCN.C(N(CC)CC)C.[CH3:23][N:24]1C[CH2:27][CH2:26][C:25]1=O>O>[CH2:25]([N:24]([CH3:23])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH:26]=[CH2:27]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCCC1=O
Agent: CC=CCN
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN(C)c1ccc([N+](=O)[O-])cc1
Yield: 96 %

Procedure:
A mixture of p-fluoronitrobenzene (2.8 g, 20 mmol), N-methylallylamine (2.10 g, 30 mmol), triethylamine (2.0 g, 20 mmol), and N-methyl-2-pyrrolidinone (NMP) (20 ml) was heated to 60°-70° C. for 5 hours in an oil bath. The mixture was diluted with distilled water (100 ml) and extracted twice with ether. The extracts were washed with distilled water and brine solution, dried over potassium carbonate and concentrated to an oil. The oil was distilled via Kugelrohr apparatus (forecut taken up to 90° C. discarded, 110°-125° C., 0.1 mm Hg) to give 3.70 g (96%) N-allyl-N-methyl-4-nitroaniline. As is, this material failed to undergo clean hydrosilation, possibly due to residual N-methyl-2-pyrrolidinone present. The remaining material was chromatographed on silica with hexane-ethyl acetate (10:1) and distilled again via Kugelrohr apparatus to give a yellow oil that underwent clean hydrosilation.
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CC=C.C[N+]1([O-])CC[O:24]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:36][C:37]([CH3:39])=[O:38]>>[OH:38][CH:37]([CH2:39][OH:24])[CH2:36][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19]
Reactant: CC(C)=O
Reactant: C=CCCCCCCCn1c(=O)c(C)cn(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Cc1cn(C)c(=O)n(CCCCCCCC(O)CO)c1=O
Yield: 91 %

Procedure:
A solution of 3-(8-nonenyl)-1-methylthymine (2.63 g, 9.9 mmol), prepared above, 4-methylmorpholine-N oxide (1.39 g, 12 mmol), and potassium osmate (IV) dihydrate (7 mg, 2×10-5 mol) in acetone (20 ml) anhours. After addition of a satura for 18 hours. After addition of a saturated aqueous solution of sodium hydrosulfite (10 ml) and 15 minutes of stirring, the reaction mixture was extracted with dichloromethane (50 ml) and with two 50 ml aliquots of dichloromethane/20% methanol. The combined organic layers were washed with water (15 ml) and saturated aqueous salt solution (15 ml), and then dried over sodium sulfate. The solvent was evaporated under vacuum, leaving a white solid residue. Recrystallization of the solid in ethanol yielded 2.68 g of 3-(8,9-dihydroxynonyl)-1-methylthymine (91% yield).
Reaction SMILES: C(O)(=[O:3])C.S(=O)(=O)(O)O.O.[C:11]([C:13]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:17])[CH:14]([CH3:16])[CH3:15])#N>C(OCC)(=O)C>[C:20]1([C:19]2[O:26][C:11](=[O:3])[C:13]([CH:14]([CH3:16])[CH3:15])([CH3:17])[N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C(C)(C#N)NC(=O)c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C1(C)N=C(c2ccccc2)OC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
40 ml of glacial acetic acid, 3.92 g (0.038 mole) of concentrated sulfuric acid and 0.36 g (0.02 mole) of water were added to 8.6 g (0.04 mole) of N-(1-cyano-1,2-dimethylpropyl)benzamide. The mixture was stirred at 80° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled. Thereto were added 100 ml of water and 100 ml of ethyl acetate for layer separation. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and concentrated to obtain 7.2 g (0.033 mole) of 2-phenyl-4-isopropyl-4-methyl-1,3-oxazol-5-one (yield=83%).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[C:21]([Cl:26])[N:20]=1.CCOC(C)=O>CN(C)C=O>[CH:1]1([N:4]([C:23]2[CH:22]=[C:21]([Cl:26])[N:20]=[C:19]([Cl:18])[N:24]=2)[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OCCCNC1CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCCCN(c1cc(Cl)nc(Cl)n1)C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
To a solution of 3-(cyclopropylamino)propan-1-ol (7 g, 60.8 mmol) and Hunig's base (31.8 mL, 182 mmol) in N,N-dimethylformamide (20 mL), was added 2,4,6-trichloropyrimidine (7.10 mL, 60.8 mmol), stirred for 3 h at 0° C. Then, EtOAc (150 mL) was added, and the organic phase was washed with water, brine, dried over Na2SO4, and concentrated. Purification via FC afforded the title compound (3.8 g).
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:21][C:20]([O:19][C:17]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:18])([CH3:23])[CH3:22]
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A 10.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 10.41 g of tert-butyl dicarbonate were added to a mixture of 50 ml of toluene, 6.95 g of potassium carbonate and 30 ml of water and stirred at 20° C. overnight, and then the organic layer was washed with 30 ml of water. The thus obtained organic layer was concentrated under a reduced pressure and then dried to obtain 14.59 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-methylpropan-2-yl ester (1H-NMR (DMSO-d6, tetramethylsilane internal standard, 80° C.): δ 1.39 (9H, s), 2.72-2.91 (2H, m), 3.28-3.32 (1H, m), 3.80-3.89 (1H, m), 6.18 (1H, s), 7.07-7.33 (9H, m), mass spectrum: m/z=310 [M +H]+ (FAB)).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C=O)s2)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 5-bromothiophene-2-carbaldehyde (1 g, 5.2 mmol) in toluene (40 mL) and ethanol (20 mL) was added (4-methoxyphenyl)boronic acid (1.59 g, 10.4 mmol), 2M Na2CO3 (14.7 mL), and Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction was purged with argon and heated at 60° C. for about 5 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (20 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 5-(4-methoxyphenyl)thiophene-2-carbaldehyde as off white solid (1 g, 87.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 7.97 (d, 1H), 7.73 (d, 2H), 7.61 (d, 1H), 7.02 (d, 2H), 3.98 (s, 3H); LC-MS m/z calcd for [M+H]+ 219.04. found 219.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)C(OS(C(F)(F)F)(=O)=O)=C(C(=O)C([O-])=O)C(C)=C2.C([O:31][CH:32]([C:38]1[C:47]([CH3:48])=[CH:46][C:45]2[C:40](=[CH:41][C:42]([Cl:49])=[CH:43][CH:44]=2)[C:39]=1OS(C(F)(F)F)(=O)=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34])(C)(C)C>>[Cl:49][C:42]1[CH:41]=[C:40]2[C:45]([CH:46]=[C:47]([CH3:48])[C:38]([C:32](=[O:31])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:39]2[C:9]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[CH:44][CH:43]=1
Reactant: Cc1cc2cc(Cl)c(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C(=O)C(=O)[O-]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)C(=O)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1

Procedure:
Ethyl 2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate was prepared in a similar manner to 2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate of Example 99, except using ethyl 2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate. 1H-NMR: (400 MHz, CDCl3): δ 8.05 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.74 (s, 1H), 7.58 (dd, J=8.6, 2.0 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.48 (s, 3H), 1.40 (t, J=7.0 Hz, 3H). 19F-NMR: (377 MHz, CDCl3): δ−73.2 (s)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])[CH3:2].[CH2:10](O)C>C1C=CC=CC=1>[CH2:1]([N:3]1[CH:10]=[N:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCNC(=O)NC(N)=O
Solvent: c1ccccc1
Product: CCn1cnc(=O)[nH]c1=O
Temperature: 60 °C
Yield: 58.7 %

Procedure:
The ethylbiuret prepared in Part A, above, [592 gm. 4.7 mole] is dispersed in 24 liter absolute ethanol and 1.6 liter benzene. This reaction mixture is heated to the reflux temperature and 3.5 liter of solvent medium is removed by distillation. The solution is cooled to 60° C. and 2090 gm. of a 25 percent solution of sodium methoxide in methanol is slowly added over an interval of five minutes. That addition is followed by the addition of 820 gm. of ethylformate. This reaction mixture is heated at the reflux temperature for three (3) hours, whereupon the solution is cooled to 38° C. and concentrated hydrochloric acid is added slowly until the pH of the solution is 2. To the acidified solution is added more (3.4 liter) benzene. Then 2 liter of the solvent medium is removed by distillation under reduced pressure and 50° C. The mixture is then heated to 75° C. and filtered in order to remove the sodium chloride produced by the reaction. The filter cake of salt is washed with hot absolute ethanol which washings are added to the filtrate. The volume of the combined filtrate and absolute ethanol washings is reduced to 5 liter by evaporation under reduced pressure at 50° C. The resulting concentrate is cooled at 5° C. for 18 hours while crystals form. The crystals are collected on a filter and washed with cold (5°) ethanol. The washed crystals are dried in an oven under reduced pressure at 50° C. for 18 hours. There is thus obtained 408 gm. of crude product having a melting point at 137° to 139° C. A further purification is achieved by dissolving the 408 gm. in 4 liter methanol at reflux temperature. This solution is concentrated by allowing the methanol to evaporate to a volume of 2 l. while being heated on a steam bath. The concentrated solution is allowed to cool slowly to 25° C. It is then chilled to 5° C. for two hours. The crystals that form are collected on a filter and the filter cake is washed with ice-cold methanol. After drying there is obtained 389 gm. (58.7 percent yield) of 1-ethyl-5-azauracil having a melting point of 141° to 142° C. A second crop of crystals is recovered from the mother liquor after further concentration and cooling.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C([O:25][C:26](=O)[C:27]([F:30])=[CH:28][O-])C.[Na+]>C(O)C>[F:30][C:27]1[C:26]([OH:25])=[N:16][C:15]([C:7]2[CH:8]=[C:9]([C:10]3[CH:14]=[CH:13][O:12][N:11]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)=[N:17][CH:28]=1
Reactant: N=C(N)c1cc(-c2ccon2)n(Cc2cccc(F)c2F)n1
Reactant: CCOC(=O)C(F)=C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ncc1F

Procedure:
This was generated via the cyclization of known intermediate 1-(2,3-difluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide (213 mg, 0.702 mmol) with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate (440 mg, 2.81 mmol) in ethanol (5.0 mL)—stirring at 90° C. for 14 hour. The solvent was removed in vacuo, and purification by silica gel chromatography (0-10% methanol in DCM) provided a mixture of the desired compound and a side-product. The mixture was then subjected to reverse-phase preparative HPLC which afforded Compound 93 (15 mg, 7.2% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]([O:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(OCC)(=O)C>CN(C)C=O>[CH:19]([O:18][C:16]([CH2:15][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)=[O:17])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccncc1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
4 g (42.06 mmol) of 4-hydroxypyridine was dissolved in 80 ml of N,N-dimethylformamide, and 8.7 g (62.92 mmol) of potassium carbonate and 16.45 g (63 mmol) of benzhydryl 2-chloroacetate were added thereto. The mixture was stirred at 60° C. for 4 hours. 200 ml of ethyl acetate was added to the reaction solution. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then treated with active carbon. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with diethyl ether to obtain 9.8 g (yield: 73%) of 1-benzhydryloxycarbonylmethyl-4-pyridone.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH2:13])=O)=[CH:6][C:5]=12.[CH3:14][C:15]([CH:17]=O)=O.[NH3:19]>C(O)C>[CH3:14][C:15]1[N:19]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)[N:12]=[N:13][CH:17]=1
Reactant: N
Reactant: CC(=O)C=O
Reactant: NNC(=O)c1ccn2ccnc2c1
Solvent: CCO
Product: Cc1cnnc(-c2ccn3ccnc3c2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (705 mg, 4.0 mmol, 1.0 equiv) and pyruvic aldehyde (40 wt % in water, 0.8 ml) in ethanol (10 ml) was stirred at room temperature for 2.5 hours. Ammonia (2M in methanol, 10 ml) was added and stirred at room temperature for 15 minutes before heating to 100 deg C. in a microwave for 60 minutes. The reaction mixture was concentrated in vacuo and dichloromethane was added. After stirring at room temperature for 15 minutes the solid (recovered starting material) was filtered off and the liquors were purified by column chromatography (0-10% methanol/dichloromethane) furnishing 200 mg of a yellow solid. MS: [M+H]+212
Reaction SMILES: [CH:1]([Cl:3])=[CH2:2].[CH2:4]=[CH:5][CH3:6].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH3:4][C:5]([C:2]1[CH:1]=[CH:12][C:7]([OH:13])=[CH:8][CH:9]=1)([C:10]1[CH:11]=[CH:12][C:7]([OH:13])=[CH:8][CH:9]=1)[CH3:6].[CH2:7]1[O:13][CH:2]1[CH2:1][Cl:3]
Reactant: C=CCl
Reactant: O=C1CCCCC1
Reactant: C=CC
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: ClCC1CO1

Procedure:
The following specimens were prepared by mixing varying parts of a vinylchloride/propylene (97/3) copolymer (Airco No. 480) and Epon 828 at room temperature in cyclohexanone solvent to give 20% solids.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=O.S1C=CC=C1.[H][H]>[Pt].CO.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: c1ccsc1
Solvent: CO
Product: Cl
Product: O=C(O)c1ccc(CN2CCN(c3ccc(Cl)nn3)CC2)cc1
Yield: 35.2 %

Procedure:
A mixture of 2 parts of 3-chloro-6-(1-piperazinyl)pyridazine, 2 parts of 4-formylbenzoic acid, 2 parts of a thiophene solution 4%, 1.5 parts of N,N-diethylethanamine and 80 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filterate was evaporated. The residue was converted into the hydrochoride salt in 2-propanol. The precipitated product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried at 50° C., yielding 1.3 parts (35.2%) of 4-[[4-(6-chloro-3-pyridazinyl)-1-piperazinyl]methyl]benzoic acid monohydrochloride; mp.>300° C. (comp. 98).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]>C(O)=O>[CH2:1]([N:4]([CH2:10][CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OC)OC)C(=O)OCC
Solvent: O=CO
Product: C=CCN(CC=O)C(=O)OCC

Procedure:
68 g (0.313 mol) of ethyl N-allyl-N-(2,2-dimethoxyethyl)-carbamate are heated with150 ml of formic acid at 100° C. for one hour. The mixture is poured onto ice and extracted several times with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.[S:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br-:1].[CH2:2]([S+:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C1CCSC1
Reactant: CCCCCC#CCC#C/C=C/C=C/CBr
Solvent: CO
Product: CCCCCC#CCC#C/C=C/C=C/C[S+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
The (E,E)-1-bromo-2,4-pentadecadien-6,9-diyne (13.8 g) was dissolved in tetrahydrothiophene (14 mL) and then treated with an aqueous methanol solution (30 mL, 9:1). The two phase system was stirred at room temperature for 40 min (clear, one phase after 5-10 min) and then concentrated, 40° at 20 mmHg and room temperature at 0.5 mm for 10 min, to give the (E,E)-2,4-pentadecadien-6,9-diyn-1-yl tetrahydrothiophenium bromide as a semi-solid (24.2 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].N1CCCCC1.[OH:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>C(O)C>[NH2:17][C:16]1[O:25][CH:26]2[C:34]3[C:30](=[CH:29][CH:28]=[C:27]2[CH:7]([C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([O:12][CH3:13])=[C:2]([Br:1])[CH:9]=2)[C:15]=1[C:14]#[N:18])[CH:31]=[CH:32][N:33]=3
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: N#CCC#N
Reactant: Oc1cccc2cc[nH]c12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2C3=CC=C4C=CN=C4C3OC(N)=C2C#N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a mixture of 5-bromoveratraldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) in ethanol (4 mL) was added piperidine (0.05 mL, 0.5 mmol) and 7-hydroxyindole (133.2 mg, 1 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel with EtOAc and hexane (1:2) as eluant, yielding 56 mg (13%) the title compound. 1H NMR (CDCl3): 8.39 (brs, 1H), 7.34–7.25 (m, 2H), 6.91 (d, J=2.1 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 6.56 (q, J=2.1 Hz, 1H), 4.80 (s, 1H), 4.67 (brs, 2H), 3.84 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:20]#[C:21]Br>CO>[C:9]1([CH:7]([CH3:8])[CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:21]([NH2:20])=[N:1]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(CC[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(CC[C@H]1COC(N)=N1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2S)-2-amino-5-phenyl-hexan-1-ol (160 mg) in methanol (11 ml) at room temperature was added sodium acetate (136 mg). The mixture was cooled to 0° C. and a solution of cyanogen bromide (96 mg) in methanol (2 ml) was added dropwise. The mixture was stirred at 0° C. for 30 min and then at room temperature overnight before being concentrated in vacuo. The residue was resuspended in tetrahydrofuran/ethyl acetate (1/2) and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/dichloromethane/methanol gradient; eluant containing 1% aq. ammonia) to yield a colourlessoil, (128 mg, 71%); MS (ISP): 219.2 ([M+H]).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C:3]=1[O:4][CH2:5][C:6]#[N:7].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:15]=2)[C:3]=1[O:4][CH2:5][C:6]#[N:7]
Reactant: OCCc1ccccn1
Reactant: Cc1cccc(COc2cccc(O)c2)c1OCC#N
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(COc2cccc(OCCc3ccccn3)c2)c1OCC#N
Reaction time: 2 h

Procedure:
To a solution of [2-methyl-6-(3-hydroxy-phenoxymethyl)-phenoxy]-acetonitrile (135 mg, 0.5 mmol, example 25) and 2-(pyridin-2-yl)-ethanol (126 mL, 0.94 mmol) in THF (2 mL) is added triphenylphosphine (262 mg, 1 mmol) followed by DEAD (118 mL, 0.75 mmol). The resulting solution is stirred for 2 h, then concentrated and the residue purified by flash chromatography (silica, 50% ethyl acetate in hexanes) to give the title compound as an oil. MS (ESI) 375 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]/[O:6][CH3:7].[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (500 mg) in carbon tetrachloride (3 ml) was cooled to 0° C., and bromine in carbon tetrachloride (1.27 mmol) was dropwise added thereto. The resulant mixture was stirred at the same temperature for 1 hour, washed with a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloroethane. The solvent was dried and evaporated, and the residue was subjected to HPLC with a mixture of hexane and ethyl acetate to give 200 mg of the objective compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH2:13]([NH2:16])[CH2:14][CH3:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCN
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with N-3-aminophenyl-N'-propylurea to generate the title compound. The N-3-aminophenyl-N'-propylurea was prepared by sequentially treating commercial 3-nitrophenylisocyanate with PrNH2 in THF at 20° C. followed by reduction with Na2S2O4 in THF/H2O at 100° C.