Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][C:15]([CH3:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([OH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>FC(F)(F)C(O)=O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[O:16][C:15]([CH3:17])([CH3:14])[O:28][C:21]=2[CH:20]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1ccc(Cl)cc1O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2ccc(Cl)cc2O1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
10 mL of trifluoroacetic anhydride and 2 mL of acetone were added to a 0° C. slurry of 4-chlorosalicylic acid (2.23 g, 13 mmol) in 16 mL of trifluoroacetic acid. The mixture was allowed to slowly warm to room temperature and stirred for 25 hours under a nitrogen atmosphere. The tan solution was concentrated under vacuum, dissolved and re-concentrated from toluene twice, and dried under vacuum. The crude solid was dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate solution and once with brine. The organic fraction was dried over sodium sulfate, and concentrated to a tan semi-solid, which was partially dissolved in 10 mL of dichloromethane and filtered to remove solids. The mother liquor was concentrated to give 1.28 g of a tan semi-solid. MS: (+) m/z 215.0/213.0 (M+1, 35/37Cl)
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([CH3:8])[N:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([CH:22]=[O:23])[N:4]([CH3:8])[N:3]=1
Reactant: Cn1nc(Br)nc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nc(Br)nc1C=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To a solution of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (500 mg, 2.08 mmol, Eq: 1.00) in tetrahydrofuran (5 ml) was added dropwise at −45° C. under argon atmosphere n-butyllithium 1.6 M in hexane (1.56 ml, 2.49 mmol, Eq: 1.2). The resulting mixture was stirred for 30 minutes at −45° C. and was then cooled to −70° C. Then dimethyl formamide (197 mg, 209 μl, 2.7 mmol, Eq: 1.3) was added dropwise. After 15 minutes the cooling bath was removed and the mixture was allowed to reach 25° C. The mixture was stirred for additional 2 hours at 25° C. The mixture was poured on water and extracted twice with ethyl acetate, the organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtrated and evaporated, affording 5-bromo-2-methyl-2H-[1,2,4]triazole-3-carbaldehyde (218 mg/55.3%) as an orange semi solid. MS: m/e=189 (M+H+)
Reaction SMILES: I[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[S:7]1[CH:11]=[CH:10][C:9]([C:2]2[N:3]=[CH:4][NH:5][CH:6]=2)=[CH:8]1
Reactant: Ic1c[nH]cn1
Reactant: OB(O)c1ccsc1
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: O
Solvent: COCCOC
Product: c1nc(-c2ccsc2)c[nH]1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 4-iodo-1H-imidazole (0.24 g, 1.25 mmol) and Pd(PPh3)4 (72 mg, 0.06 mmol) in DME (12.5 mL) was degased by purging with argon for 10 min. Thiophene-3-boronic acid (0.32 g, 2.50 mmol) and Na2CO3 (2.5 mL of a 2M solution in water) were added. The mixture was heated to reflux for 18 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (4% MeOH/CH2Cl2, silica gel) to give 0.16 g of the desired product as an off-white solid. MS(ES+) m/z 151.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:15]#[N:16].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>C1(C)C=CC=CC=1>[CH2:8]([NH:7][C:4]1[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[NH:6][N:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(OCC)N(C)C
Reactant: N#Cc1c(NCc2ccccc2)n[nH]c1N
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(NCc2ccccc2)c1C#N
Temperature: 25 °C

Procedure:
Under a N2 atmosphere, a suspension of 74.3 g (348 mmol) of 5-amino-3-benzylamino-1H-pyrazole-4-carbonitrile in 1.0 liter of toluene is boiled under reflux for 2 hours with 70.1 ml (95%; 409 mmol) of N,N-dimethylformamide diethyl acetal. Cooling to RT, filtering with suction and washing with diethyl ether yield N'-(3-benzylamino-4-cyano-1H-pyrazol-5-yl)-N,N-dimethylformamidine; m.p. 197-200° C.; TLC: Rf =0.50 (ethyl acetate).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[C:21][CH2:22][CH2:23]O)[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CN(S(F)(F)[F:31])C.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[C:21][CH2:22][CH2:23][F:31])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(C(=O)c1ccc(F)c(C#CCCO)c1)c1ccc(OC(F)F)cc1
Reactant: CN(C)S(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C(=O)c1ccc(F)c(C#CCCF)c1)c1ccc(OC(F)F)cc1
Temperature: -78 °C

Procedure:
In a 100 mL round bottom dissolve 1-(4-Difluoromethoxy-phenyl)-2-[4-fluoro-3-(4-hydroxy-but-1-ynyl)-phenyl]-ethane-1,2-dione (0.670 g, 1.85 mmol) was dissolved in dichloromethane (40 mL) and chilled to −78° C. Add (Dimethylamino)sulfur trifluoride (MeDAST; 2.99 g, 22.4 mmol) was introduced via syringe injection. After 30 minutes dry-ice bath was removed. After 2 hours at ambient temperature the crude reaction was carefully poured into a 500 mL beaker containing 200 cc ice-chips and sodium bicarbonate. An attempted diethyl ether extraction with diethyl ether resulted in emulsion. Sodium chloride was added to break emulsion. Organic layer was concentrated to a residue, and loaded directly on top of an 80 gm chromatography column. Purification [YAMAZEN W-Prep 2XY using automatic gradient elution: 3% EtOAc/hexanes (hold 4 min) to 24% EtOAc (in 12 min), hold 8 minutes] afforded oil that begins to solidify as a wax 360 mg (53%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].B(F)(F)F.CCOCC.[CH3:20][C:21]1([CH:27]=[CH2:28])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>O1CCOCC1.CCOCC>[CH3:20][C:21]1([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:27][CH2:28][C:4]2[C:3](=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[CH3:9])[O:10]1
Reactant: C=CC1(C)CCC(=O)O1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(C)c2c(c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 2,3,5-trimethylphenol (0.01 mol) and boron trifluoride diethyl etherate (0.016 mol) in dioxane (10 mL, dried on sodium) in a flask was added γ-methyl-γ-vinylbutyrolactone (0.016 mol) in dioxane (5.0 mL) via syringe pump over 50 min at 110° C. (oil bath, reflux) under nitrogen. The reaction mixture was cooled to room temperature and diluted with ether (200 mL), then washed with water (100 mL, 2×50 mL) and dried over sodium sulfate. Ether was then removed in vacuum. The residue was dissolved in methanol (30 mL), and solvent was removed in vacuum. The reaction mixture was purified by flash column chromatography on silica gel (eluant ethyl acetate/hexane, 1:1). Fractions containing the desired chroman were pooled, solvent was removed, and the compound was crystallized from ethyl acetate/hexane to afford a white crystalline product in a yield of 40%. M.P.: 148-149° C.
Reaction SMILES: [O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3].[N+]([O-])([O-])=[O:9].[In+3:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O>O>[OH-:1].[In+3:12].[OH-:9].[OH-:14].[O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3]
Reactant: O=[N+]([O-])[O-]
Agent: O=[Sb](=O)O[Sb](=O)=O
Agent: [In+3]
Solvent: O
Product: [OH-]
Temperature: 25 °C

Procedure:
900 g of water was added to 600 g of the diantimony pentoxide sol (specific gravity: 1.198, Sb2O5 concentration: 18.4 wt %) prepared in Preparation Example 1 for dilution. Then, an aqueous indium nitrate solution having 242.2 g of indium nitrate (In(NO3)3.3H2O, In2O3 content: 39.1 wt %, guaranteed reagent, manufactured by Mitsuwa Kagaku Yakuhin K.K.) dissolved in 200 g of water, was added thereto with stirring at room temperature. Then, the mixture was heated at 90° C. for 6 hours to obtain a mixed slurry of indium hydroxide and diantimony pentoxide. This slurry had an In2O3 concentration of 4.9 wt %, a Sb2O5 concentration of 5.7 wt % and an In2 O3 /Sb2O5 molar ratio of 1.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCCC>C(OC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10][Br:15])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: COC(C)=O
Product: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 80.4 %

Procedure:
A mixture of 5-methyl-2-nitro-benzoic acid methyl ester (93.95 g, 481.35 mmol), 1,3-dibromo-5,5-dimethylhydantoin (75.70 g, 264.74 mmol), in methyl acetate (550 mL) was heated at 78° C. for 40 minutes while stirred with a mechanical stirrer. Then a solution of 2,2′-azobisisobutyro-nitrile (3.95 g, 24.07 mmol) in methyl acetate (80 mL) was added, and the mixture was heated at about 75° C. for 13 hours. The mixture was allowed to cooled to 15° C. and stirred for 2 hours to age the precipitate. The suspension was filtered, washed with 10° C. methyl acetate (2×50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL). The organic layer was washed with 2% brine (2×500 mL) and water (2×500 mL), and concentrated to about 2 volumes. To the mixture, was added t-butyl methyl ether (or MTBE, 300 mL). The mixture was heated at about 70° C. for 15 minutes, cooled to about 53° C. over one hour, seeded with the product (about 250 mg, or simply re-crystallized) at 45° C., then at 20˜25° C., while blowing nitrogen with a glass pipette overnight. The resulting solid was filtered via a medium pore-sized funnel, washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 5-bromomethyl-2-nitro-benzoic acid methyl ester as an off-white solid (58.3 g, 44.0% yield). The solid was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:36][C@H:35]2[NH:37][CH2:38][C@@H:30]1[CH2:31][CH:32]=[CH:33][CH2:34]2.CCN(C(C)C)C(C)C>C(O)C>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][N:37]2[CH2:38][CH:30]3[N:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)[CH2:36][CH:35]2[CH2:34][CH:33]=[CH:32][CH2:31]3)=[CH:7][CH:8]=1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC(COc1cccc2[nH]c3ccccc3c12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
(S)-4-Oxiranylmethoxy-9H-carbazole (18.5 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [C:1]([NH:6][C:7]1[O:8][C:9]([CH3:12])=[CH:10][N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:16]([N:6]([C:7]1[O:8][C:9]([CH3:12])=[CH:10][N:11]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1cnc(NC(=O)C(C)C)o1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C(=O)C(C)C)c1ncc(C)o1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2-isobutyramido-5-methyloxazole (2.10 g., 0.0124 mol), prepared as above, was dissolved in dry dimethylformamide (10 mls.) and cooled to below 5° C. To this was added sodium hydride (0.70 g., 0.0145 mol.) portionwise, keeping the temperature below 5° C. After the addition, the mixture was stirred for a further 30 minutes at 5° C and then allowed to warm to room temperature. The iodobutane (5.0 g., 0.0271 mol.) was added. The mixture was stirred overnight, the solvent was evaporated under reduced pressure and the residue was partitioned between water (50 mls.) and ether (50 mls.). The organic phase was then washed with 2N HCl (2 × 25 mls.), water (1 × 25 mls.), 10% aqueous sodium carbonate (3 × 25 mls.) and water (3 × 25 mls.). The organic phase was then dried over magnesium sulphate and evaporated under reduced pressure. The residue was distilled from a Kugelrohr, air bath temperature 100° C/0.1 mm. Yield = 1.74 g. (62%).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O.CC(C)=O.[Cu]>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Cc1ccc(O)cn1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cu]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1ccc(Oc2cccc(C(F)(F)F)c2)cn1

Procedure:
3.68 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylformamide, and 5.65 g of m-bromobenzotrifluoride and 300 mg of copper powders were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 120° C. for 15 hours while stirring. After cooling, the reaction mixture was diluted with 40 ml of acetone and filtered. The filtrate was immediately dried to solidify, and 100 ml of chloroform and 50 ml of water were added thereto. The mixture was adjusted to a pH of 9 with 5 N sodium hydroxide, and any insoluble matter was again separated by filtration. The resulting chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.1 g of oily 5-(m-trifluoromethylphenoxy)-2-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.Cl[C:34]([NH:37][NH2:38])(Cl)[CH3:35].NN>CO>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]2[CH:35]=[CH:34][N:37]=[N:38]2)=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: CC(Cl)(Cl)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-n1ccnn1
Temperature: 50 °C
Yield: 30.3 %

Procedure:
Following the procedure of Harada et al., Heterocycles 1998, 48, 695-702, to a solution of 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.400 g, 1.8 mmol) in 5 ml methanol at 0° C. was added trimethylamime (0.308 g, 3.0 mmol) and hydrazine 1,1-dichloroethyl hydrazine tosylate (0.388 g, 1.4 mmol). The solution was warmed to 50° C. After 4 h the mixture was concentrated in vacuo and extracted with CH2Cl2. The combined organics were washed with H2O, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via flash chromatography (94:6 CH2Cl2/MeOH) afforded 5-(2-isopropyl-4-methoxy-5-[1,2,3]triazol-1-yl-phenoxy)-pyrimidine-2,4-diamine (0.145 g, 31%) as a white solid; [MH]+=342.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:18])=[CH:7][C:8]([S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:5][C:6]1([CH3:18])[C:12]2[C:11](=[CH:16][CH:15]=[C:14]([Br:17])[CH:13]=2)[S:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Sc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=O)Sc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred, ice-cooled suspension of 15.9 g (119 mmol) of aluminum chloride in 140 ml of methylene chloride was added under nitrogen a solution of 21.64 g (79.9 mmol) of S-(4-bromophenyl) 3,3-dimethyl-thioacrylate (Compound 30) in 100 ml of methylene chloride. The mixture was then stirred at room temperature for 72 h and then poured into 250 g of an ice and brine mixture. The mixture was extracted with methylene chloride and the combined organic extracts were washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue recrystaliized from hexanes to give the title compound as white crystals. PMR (CDCl3): & 1.40 (6H, s), 2.67 (2H, s), 7.31-7.4.0 (3H, m). MS exact mass, m/e 269.9714 (calcd. for C11H11SOBr, 269.9714).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J31) (304 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (380 mg, 71%).
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:16][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCC(=O)OCCN(C)C
Yield: 62.6 %

Procedure:
A solution of 91.35 g (0.40 mol) of myristic acid, 35.7 g (0.40 mol) of 2-dimethylaminoethanol, 0.5 g of p-toluenesulfonic acid and a suitable volume of toluene was heated at reflux for approximately 48 hours in a 1-neck 3 liter flask equipped with Dean-Stark trap and condenser. At the end of this time, 7.0 ml of water had collected in the trap. The solution was cooled, stirred with K2CO3, filtered and concentrated. The residue was distilled to give 75.0 g of product; bp=145°-50° C./0.50 mm.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:9]1([C:5]2[CH:4]=[C:3]([CH2:2][N:25]3[CH2:24][CH:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:27][CH2:26]3)[CH:8]=[CH:7][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1cccc(-c2ccccc2)c1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C1=C(c2ccccc2)CCN(Cc2cccc(-c3ccccc3)c2)C1
Temperature: 25 °C

Procedure:
To a solution of 45 mg of 3-chloromethylbiphenyl in 5 mL of chloroform was added 50 mg of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 0.5 mL triethylamine. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature, washed successively with 50 mL aliquots of dilute sodim hydroxide and brine. The chloroform was removed by evaporation under reduced pressure to yield 3-phenyl[(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]benzene which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 3-[(4-1,2,3,6-tetrahydropyridin-1-yl)methyl]biphenyl hydrochloride (Compound 3), mp 236-238° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC(O)=O.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(O)c(Br)c1
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a stirred solution of methyl 4-hydroxybenzoate (10.0 g, 84.935 mmol) in CCl4 (30 mL) was added AcOH (20 mL, 2 Vol). Br2 (1.80 mL, 71.428 mmol) was then added slowly at 0° C. After the addition was completed, the reaction mixture was brought to RT and stirred for 8 h. Reaction mixture was quenched with water (50 mL), neutralized with saturated NaHCO3 solution and extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc-95% hexanes to afford methyl 3-bromo-4-hydroxybenzoate (10.0 g, 66%) as a brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: CNC
Reactant: OCCOCCOCCCl
Product: CN(C)CCOCCOCCO
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Commercial Cl(CH2CH2O)3H (abb. ClE3H) (2.0 mole) and dimethylamine (20.0 mole) were mixed in a flask (3.0 l) fitted with a condenser and stirred (RT) for 30 hours. TLC (Si-gel) examination showed the complete consumption of the ClE3H. Excess dimethylamine was removed by two consecutive evaporations under reduced pressure. The residual material was reconstituted in CHCl3, dried (MgSO4), filtered and evaporated to dryness to produce the product, 8-dimethylamino-3,6-dioxaoctanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[OH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[NH:16][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]1[CH3:15]
Reactant: Nc1ccccc1CO
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Product: CC1CN(C(=O)OC(C)(C)C)CCC1Nc1ccccc1CO

Procedure:
The product was prepared from N-tert-butoxycarbonyl-3-methyl-4-piperidone (4.3 g) and 2-amino-benzyl alcohol (2.59 g) using the method of example 7 step (i). Yield 6.3 g as a mixture of diastereoisomers.