Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].[O:13]1[CH2:15][CH:14]1[CH2:16][O:17][C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.O.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:15][CH:14]([OH:13])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]=12
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: COc1ccccc1OCCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
2-(2-Methoxyphenoxy)ethylamine (III) (4.89 g) was heated to about 100° C., after which 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (3.31 g) was added portionwise. After approximately 20 minutes, the reaction mixture was cooled to about 70° C., after which water (25 ml) and ethyl acetate (15 ml) were added. The pH of the two-phase mixture was then adjusted to 5 with 2 N hydrochloric acid. The solid that formed, Carvedilol hydrochloride hydrate, is filtered, washed with water (20 ml) followed with ethylacetate (15 ml). The resulting material is reslurried in ethylacetate (50 ml) and water (20 ml) containing 5% Sodium carbonate until the pH reached 7.5. The organic phase was separated and dried over sodium sulfate. The dried solution was concentrated to a turbid solution and cooled overnight to about 4° C. Precipitated carvedilol was isolated by filteration and crystallized from isopropanol.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=O)[CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=1[CH3:19].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[CH3:12][C:13]1[CH:14]=[C:15]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:7])[CH2:10][CH2:11]2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: C1CSCCN1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(Br)cc1C
Product: Cc1ccc(N2CCC(C(=O)N3CCSCC3)CC2)cc1C

Procedure:
The title compound was prepared from commercially available ethyl isonipecotate, 3,4-dimethylbromobenzene as the aryl halide, and thiomorpholine as the secondary amine utilizing general procedures A and B described above. 1H NMR (300 MHz, CDCl3) 1H NMR (CDCl3) δ 7.01 (d, J=7.8 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 6.70 (dd, J=2.3, 7.8 Hz, 1H), 3.90 (m, 2H), 3.80 (m, 2H), 2.96 (m, 1H), 2.89 (m, 1H), 2.71-2.50 (m, 7H), 2.23 (s, 3H), 2.18 (s, 3H), 2.04 (dd, J=2.6, 12.2 Hz, 1H), 1.93 (dd, J=3.3, 12.3 Hz, 1H), 1.80 (m, 1H), 1.76 (m, 1H). ESI MS: 319.4 (MH+).
Reaction SMILES: [I-].C([N+:9]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10]1)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])N.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[C:17]1([CH3:22])[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:9]([C:28]2[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=2)[CH2:10]1
Reactant: Cc1ccccc1C1C[N+](C)(Cc2ccccc2)CCC1=O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCC(=O)C(c3ccccc3C)C2)cc(OC)c1OC
Yield: 78.3 %

Procedure:
A slurry of 1-benzyl-1-methyl-4-oxo-3-o-tolyl-piperidinium iodide (1000 mg) in water (5 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (395 mg) and anhydrous potassium carbonate (37 mg) in ethanol (10 ml). The reaction was heated to reflux over night. Water was added and the reaction was extracted four times with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a red-brown oil, which was purified by flash chromatography (diethyl ether) to give the product as a yellow oil (600 mg). MS (ESI): 356.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4](C(Cl)Cl)[N:3]=1.ClC1C=C(Cl)C=C([C:20]([Cl:23])([Cl:22])F)N=1.[Cl:24]C1C=C(Cl)C=C(C(Cl)(Cl)Cl)N=1>>[Cl:24][C:4]1[CH:5]=[C:6]([CH:20]([Cl:23])[Cl:22])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: FC(Cl)(Cl)c1cc(Cl)cc(Cl)n1
Reactant: Clc1cc(Cl)nc(C(Cl)(Cl)Cl)c1
Reactant: Clc1cc(Cl)nc(C(Cl)Cl)c1
Product: Clc1cc(C(Cl)Cl)cc(Cl)n1

Procedure:
The 2,4-dichloro-6-(dichloromethyl)pyridine and the 2,4-dichloro-6-(dichlorofluoromethyl)pyridine reactants can be prepared by following the above procedure, employing 2,4-dichloro-6-(trichloromethyl)pyridine as the starting material.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[CH3:4]
Reactant: COc1ccc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C/C=C/c1ccc(OC)nc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-methoxy-3-pyridyl)-4-penten-2-amine (2.90 g, 9.45 mmol) in dichloromethane (20 mL) was treated drop-wise over 15 min with trifluoroacetic acid (15 mL). After stirring for 30 min, the solution was concentrated to a yellow-orange oil. The residue was diluted with saturated aqueous NaCl solution (15 mL), cooled to 0-5° C., and basified with 10% aqueous NaOH solution (22 mL). The mixture was extracted with CHCl3 (5×25 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, and concentrated under vacuum to give a light-yellow oil (1.88 g). The crude product was purified by column chromatography on silica gel (70-230 mesh) (150 g), eluting with a CH3OH—NH4OH step-wise gradient (100:1→15:1 in increments of 25:1). Fractions containing the product (Rf 0.28 in CHCl3—CH3OH-Et3N (50:1:1)) were kept separate from those containing an impurity (Rf 0.35) and were combined and concentrated to give 0.76 g of a light-yellow oil. Impure fractions were combined and concentrated to give 1.20 g of light-yellow oil. The latter material was re-chromatographed on a new silica gel column (75 g) using the same CH3OH—NH4OH gradient elution protocol. Impure fractions were combined and concentrated to give 1.08 g of light-yellow oil. The latter material was re-chromatographed (6 times) on a new silica gel columns (45 g and 25 g) using CHCl3—CH3OH-Et3N step-wise gradient (16:1→1:1 in CHCl3—CH3OH, with each gradient step containing 1% Et3N). All fractions containing the product were combined and concentrated under vacuum to give 1.368 g (70.2%) of a light-yellow oil.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][N:19]([CH2:21][CH2:22][SH:23])[CH3:20].[OH-].[Na+]>CN(C)C=O.Cl.O>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][S:23][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3
Reactant: CN(C)CCS
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CSCCN(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
To a suspension of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1. 765 g) in dimethylformamide (60 ml), hydrochloric acid salt of 2 (dimethylamino)ethylmercaptan (4.25 g) and caustic soda (2.40 g) in water (20 ml) were added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was combined with water, and extracted with chloroform. The extract was washed with NaCl solution twice and dried and condensed. The residue was crystallized from chloroform--n-hexane to obtain 1.741 g of the title compound as white powder (mp.: 163°-165° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=[O:19])[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.ClS([N:24]=[C:25]=O)(=O)=O.CN(C=O)C.C([O-])(O)=O.[Na+].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:25]#[N:24])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=[O:19])[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reaction time: 0.17 h

Procedure:
A flask is charged with 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole (10 g, 36.9 mmol) and acetonitrile (1 L), and chlorosulfonyl isocyanate (15.68 g, 111 mmol) is added at 0° C. The mixture is stirred for 10 min. DMF (18.9 g, 259 mmol) is added at 0° C. The mixture is stirred for 1.5 h. Saturated NaHCO3 (20 mL) and triethylamine (51.5 mL, 369 mmol) are added to the reaction mixture, which is stirred for 10 min. The mixture is concentrated in vacuo to give a residue which is purified by silica gel flash chromatography eluting with a 0 to 5% methanol-DCM gradient to give 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. MS (ESI) m/z 296.0, 297.8 (M+H)+.
Reaction SMILES: Br.[C:2]([OH:5])(=[O:4])[CH3:3].C(OC([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([Cl:33])[C:23]=2[N:22]=[CH:21]1)=O)C1C=CC=CC=1>>[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([Cl:33])[C:23]=2[N:22]=[CH:21]1.[C:2]([O-:5])(=[O:4])[CH3:3]
Reactant: O=C(NCCCn1cnc2c(Cl)nc3ccccc3c21)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)[O-]
Product: NCCCn1cnc2c(Cl)nc3ccccc3c21
Reaction time: 1.5 h

Procedure:
3 ml of 33% hydrogen bromide-acetic acid was added to 0.12 g (0.304 mmol) of 1-[3-(benzyloxycarbonylamino)propyl]-4-chloro-1H-imidazo[4,5-c]quinoline and the mixture was stirred at room tempterature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, a 1N sodium hydroxide aqueous solution and brine were added to the residue and the solution was extracted five times with chloroform. The organic phase was dried (Na2SO4), the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol:32% acetic acid=12:6:1 (v/v)) to obtain 60 mg (0.187 mmol) of 1-(3-aminopropyl)-4-chloro-1H-imidazo[4,5-c]quinoline·acetate shown below as a pale yellow solid. ##STR32## Its spectroscopic data are as follows: 1H-NMR (CD3OD) δ (ppm): 1.94 (3H, s), 2.39 (2H, m), 3.12 (2H, t, J=7.8 Hz), 4.82 (2H, t, J=7.2 Hz), 7.70 (2H, m), 7.97 (1H, d, J=8.0 Hz), 8.27 (1H, d, J=8.0 Hz), 8.41 (1H, s).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=O>>[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1/[CH:6]=[CH:47]/[C:46]1[CH:45]=[C:44]([CH2:43][CH2:42][CH2:41][N:32]2[C:33](=[O:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]2=[O:30])[CH:51]=[CH:50][CH:49]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: COc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COc1ccccc1/C=C/c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
2-Methoxybenzyltriphenylphosphonium bromide was coupled with phthalimide 29 to give (E)-2-(3-(3-(2-methoxystyryl)phenyl)propyl)isoindoline-1,3-dione as a white solid. Yield (0.5590 g, quant.), trans-/cis-isomer ratio 1:1. Trans-isomer: 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.88 (m, 4H), 7.52-7.65 (m, 5H), 6.69-7.41 (m, 4H), 6.57 (d, J=16.8 Hz, 1H), 3.76 (s, 3H), 3.52 (t, J=6.8 Hz, 2H), 2.48 (t, J=8.0 Hz, 2H), 1.91-1.99 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14]O)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.C(N(S(F)(F)[F:24])CC)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14][F:24])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2
Reactant: CC(C)(CO)c1cc(F)c2c(=O)[nH]ccc2c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(CF)c1cc(F)c2c(=O)[nH]ccc2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
8-fluoro-6-(1-hydroxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (114 mg, 485 μmol) was dissolved in DCM (dry) and cooled to −78° C. under argon. To this solution was added the diethylaminosulfur trifluoride (90 μl, 678 μmol) and the reaction was stirred for about 10 min before removal of the cooling bath. The reaction was warmed to ambient and stirred at this temperature for 2 hrs. To the reaction mixture was added 25 ml water and 20 ml DCM. The mixture was shaken and the organics collected. The organics were washed with 25 ml brine. The aqueous phase was extracted (2×20 ml DCM). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by preparative tlc (2 plates, eluted with 4.5% MeOH/DCM) to afford 92 mg of the desired product as an off-white powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[N:7][C:6]=2[CH:26]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:26]1[C:6]2[N:7]=[C:8]([C:10]#[CH:11])[O:9][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccn1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C#Cc1nc2c(-c3ccccn3)cccc2o1
Yield: 224 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mmol), 2-bromo-pyridine (0.66 ml, 98%, 6.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (21.1 mg, 30 μmol) and copper (I) iodide (1.2 mg, 6 μmol) in triethylamine (12 ml) was heated at 90EC, under argon, for 1.5 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (100 ml). The organics were washed with water (50 ml), 1 N HCl (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), dried (Na2SO4) and evaporated in-vacuo to give 2.96 g (104.2%) of crude pyridyl ethynyl benzoxazole. The crude benzoxazole was purified by column chromatography (SiO2; dichloromethane), and the product crystallized from methanol and suspended in hot water. The resulting crystals were collected, washed, and dried to give 1.49 g (52.5%) of the title compound (mp 138-9EC).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([C:16]([O:18]CC)=O)=[CH:14][N:13]=[C:12]([S:21][CH3:22])[N:11]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][NH2:33]>FC(F)(F)CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:10]3[N:11]=[C:12]([S:21][CH3:22])[N:13]=[CH:14][C:15]=3[C:16](=[O:18])[N:32]([C:26]3[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])[N:33]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1cccc(Cl)n1
Agent: Cl
Solvent: OCC(F)(F)F
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)nc(-c3cccc(Cl)n3)c2n1
Temperature: 108 °C

Procedure:
To a suspension of Example 175A (512 mg, 1.52 mmol) in 2,2,2-trifluoroethanol (15 mL) was added 2,6-dichlorophenylhydrazine hydrochloride (324 mg, 1.516 mmol). The mixture was heated in a sealed tube at 108° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine. The organic phase was concentrated. The residue was separated by flash chromatography (15-50% gradient ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 451 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:14][CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23]>CCCCCC>[CH3:14][CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:13][CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1cc(CCCO)ccc1O
Solvent: CCCCCC
Product: COc1cc(CCCOC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 95.7 %

Procedure:
3-(3-Methoxy-4-hydroxyphenyl)propyl alcohol (833 mg, 4.57 mmol), 8-methylnonanoic acid (753 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr while reducing the pressure by an aspirator. The reaction mixture was allowed to cool to room temperature, n-hexane (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. N-hexane (50 ml) was added, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2), saturated brine (25 ml), 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(3-methoxy-4-hydroxyphenyl)propyl 8-methylnonanoate (1.40 g, yield 95.4%) as a colorless oil.
Reaction SMILES: C(Cl)(=O)N.[Cl:5][C:6]([Cl:11])([Cl:10])[C:7]([NH2:9])=[NH:8].C[O:13][C:14](=O)[CH2:15][C:16]([CH3:18])=O>>[OH:13][C:14]1[CH:15]=[C:16]([CH3:18])[N:9]=[C:7]([C:6]([Cl:11])([Cl:10])[Cl:5])[N:8]=1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: COC(=O)CC(C)=O
Agent: NC(=O)Cl
Product: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1

Procedure:
The pyrimidinyl carbamate compounds of the present invention may be prepared by reacting trichloroacetamidine with the corresponding acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carbamoyl chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with methylacetoacetate to form 4-hydroxy-6-methyl-2-trichloromethylpyrimidine. In equation (B), the 4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with dimethylcarbamoyl chloride to form 6-methyl-2-trichloromethyl-4-pyrimidinyl dimethylcarbamate. ##STR3##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C@H:10]([C:12]([O:14]C)=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.CO.O[Li:33].O>O>[Li+:33].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C@H:10]([C:12]([O-:14])=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [Li]O
Reactant: COC(=O)[C@H](C)N(Cc1cccc(OC)c1)c1ccc(F)c(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CN(c2ccc(F)c(Cl)c2)[C@@H](C)C(=O)[O-])c1
Product: [Li+]
Reaction time: 24 h

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)-N-(3-methoxybenzyl)alaninate (6-1, 0.510 g, 1.450 mmol) in a 3:1:1 mixture of THF:MeOH:H2O (100 mL) was treated with LiOH hydrate (0.067 g, 1.595 mmol) then stirred 24 h. Upon completion, the reaction mixture was concentrated under vacuum to yield N-(3-chloro-4-fluorophenyl)-N-(3-methoxybenzyl)alanine lithium salt (6-2). MS 338.2 found 338.8 (M+H+) required.
Reaction SMILES: [CH2:1]([C:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[CH:17][C:18]([OH:22])=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH2:29]=O.[CH3:31][NH:32][CH3:33]>C(O)(=O)C>[CH3:31][N:32]([CH2:29][C:19]1[C:20]2[CH:21]=[C:12]3[CH2:11][N:10]4[C:23](=[CH:24][C:25]5[C:3]([CH2:1][CH3:2])([OH:28])[CH2:4][C:5](=[O:27])[O:6][CH2:7][C:8]=5[C:9]4=[O:26])[C:13]3=[N:14][C:15]=2[CH:16]=[CH:17][C:18]=1[OH:22])[CH3:33]
Reactant: CCC1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CCC1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1

Procedure:
A suspension of 5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (260 mg, 0,69 mmol) in acetic acid (15 ml) is treated with aqueous formaldehyde at 37% (500 μl) and aqueous dimethylamine at 40% (500 μl) and the resultant mixture is agitated at ambient temperature for 16 hours. The reaction mixture is concentrated to dryness and the residue is purified by column chromatography (SiO2, CH2Cl2/MeOH: 100/0 to 90/10) followed by crystallization from acetonitrile, which produces 102 mg of sought compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][C@@H:9]([O:10][CH3:11])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:11][O:10][C@@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: [H][H]
Reactant: CO[C@@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 2.5 h

Procedure:
(3R,3aR,6R,6aS)-(9H-Fluoren-9-yl)methyl 3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (5b). Ethanol (30 mL) was added dropwise to a mixture of 10% palladium on charcoal (200 mg) and syn-/anti-epoxides respectively (605 mg, 2.06 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 2.5 hours then filtered through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain the crude (3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.[O:37]=[CH:38][C@@H:39]([CH2:41]O)[OH:40]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH:41]([C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)[C@H:39]([OH:40])[CH2:38][OH:37])[CH2:27][CH2:28]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CCN1CCNCC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C[C@H](O)CO
Reactant: OB(O)c1ccco1
Solvent: CCO
Solvent: O
Product: CN(C[C@@H](CCN1CCN(C(c2ccco2)[C@H](O)CO)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: 50 °C

Procedure:
2.08 g N-[(2S)-2-(3,4-dichlorophenyl)-4-(piperazinyl)butyl]-N-methylbenzamide (preparation see above under 1C) was dissolved in 100 ml ethanol and heated to approx. 50° C. 740 mg 2-furanboronic acid and 550 mg of an 80%-strength solution of D-glyceraldehyde in water were added to this initial solution. The resulting solution was heated to boiling at reflux for 10 hours. Then excess solvent was evaporated in a vacuum. Purification of the residue by column chromatography on silica gel (mobile solvent: dichloromethane/EtOH/NH4OH 87/11/2) yielded 2.1 g of the title compound as a beige foam, optical rotation [α]D20=−6.1° (c=1 in methanol); 1H-NMR (CDCl3, RT): 3.65 (d, 1H); 4.23 (ddd, 1H); 3.72 (dd, 1H); 3.78 (dd, 1H); 6.27 (d, 1H); 6.37 (1H); 7.42 (1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[Br:17]N1C(=O)CCC1=O>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:17])=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1-c1ccccn1
Product: COc1ccc(Br)c(OC)c1-c1ccccn1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 2 using 1,3-Dimethoxy-2-(Pyrid-2-yl)benzene 37 and N-bromosuccinimide to yield 38.