Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(Cl)cc2)n1
Yield: 28.1 %

Procedure:
A stirred mixture of 8.0 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 3.8 g of p-chloroaniline and 3.2 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate until precipitation resulted. Recrystallization of this material from 95% ethanol afforded 3.0 g of product, mp. 109°-112°C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:66]1[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][NH2:73])[CH:67]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([NH:73][CH2:72][C:68]4[CH:67]=[N:66][CH:71]=[CH:70][CH:69]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.11 g, 0.30 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added 1-hydroxybenzotriazole (HOBt) (0.08 g, 0.60 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.19 g, 0.60 mmol), N,N-diisopropylethylamine (0.23 g, 1.80 mmol) and pyridin-3-ylmethanamine (0.05 g, 0.45 mmol). The resulting mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was diluted in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with 2-8% methanol in dichloromethane to afford the title compound as a colorless solid (0.09 g, 70%): mp 67-70° C. (hexanes/diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.57 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.40-7.34 (m, 3H), 7.18 (dd, J=8.8, 8.8 Hz, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.40 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.1, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.1, 6.2 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.5 (d, 1JC-F=244 Hz), 161.8, 157.2, 154.9, 151.2, 148.8, 148.0, 135.1, 135.1, 133.1 (d, 4JC-F=3 Hz), 130.0 (d, 3JC-F=8 Hz), 123.5, 117.6, 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 40.4, 18.4, 17.1; MS (ES+) m/z 439.9 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)SC)#[N:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C(#N)C>[C:1]([N:3]=[C:4]([NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[NH:22][CH2:18][CH2:19][CH2:20][CH3:21])#[N:2]
Reactant: CSC(=NC1CCCc2ccccc21)NC#N
Reactant: CCCCN
Solvent: CC#N
Product: CCCCNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 100 h

Procedure:
A solution of 12.3 g of N-cyano-N'-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 20 ml of n-butylamine in 100 ml of acetonitrile was heated at reflux with stirring for 100 hours. The solvent was removed by evaporation in vacuo. The residual oil was dissolved in methylene chloride, and the solution was washed with three 80 ml portions of 3N hydrochloric acid and then dried over anhydrous sodium sulfate. The methylene chloride was removed by evaporation in vacuo, leaving as residue N"-cyano-N-n-butyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as 9.73 g of a pale yellow, viscous oil.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 ml single neck round bottom flask, under a nitrogen atmosphere, 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (300 mg, 0.572 mmol) was added to anhydrous methylene chloride (20 ml). To this was added trifluoroacetic acid (0.44 ml, 652 mg, 5.72 mmol). The resulting mixture is stirred overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography. The solvents were removed in vacuo.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[O:16]([CH2:23][C:24](OCC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:10]1([S:7]([CH2:6][C:24](=[O:25])[CH2:23][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)COc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)CS(=O)(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 14 h

Procedure:
n-Butyllithium (8.5 ml, 1.6M in hexane) was added at -72° C. to a solution of methylphenyl sulfone (2.14 g, 13.7 mmol) in 80 ml of tetrahydrofuran. The reaction mixture was then allowed to warm slowly to -20° C. and maintained at this temperature for 25 minutes. It was then recooled to -72° C. and ethyl phenoxyacetate (1.48 g, 8.22 mmol) was added dropwise. The cooling bath was removed, the mixture was stirred at 20° C. for 14 hrs. and then poured into 100 ml of saturated NH4Cl and extracted with diethyl ether. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The crude residue was purified by column chromatography (silica gel, methylene chloride) giving 1-phenylsulfonyl-2-oxo-3-phenoxypropane, the compound of formula (2a), 800 mg.
Reaction SMILES: [CH2:1]([O:4]N1C(=O)N2C[C@H]1C=C(C)[C@H]2C(N)=O)C=C.[CH2:18]([O:21][NH:22][C@H:23]1[CH2:28][NH:27][C@H:26]([C:29]([NH2:31])=[O:30])[C:25]([CH:32]([CH3:34])[CH3:33])=[CH:24]1)[CH:19]=[CH2:20]>>[CH2:18]([O:21][N:22]1[C:1](=[O:4])[N:27]2[CH2:28][C@H:23]1[CH:24]=[C:25]([CH:32]([CH3:34])[CH3:33])[C@H:26]2[C:29]([NH2:31])=[O:30])[CH:19]=[CH2:20]
Reactant: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(N)=O
Reactant: C=CCON[C@@H]1C=C(C(C)C)[C@@H](C(N)=O)NC1
Product: C=CCON1C(=O)N2C[C@H]1C=C(C(C)C)[C@H]2C(N)=O
Yield: 77 %

Procedure:
(2S,5R)-6-(allyloxy)-3-isopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (0.46 mg, 77%) was prepared a similar manner as described in Intermediate 86 as a pale yellow oil, using (2S,5R)-5-(allyloxyamino)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 96, 0.54 mg, 0.23 mmol) as a starting material.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -3 °C
Reaction time: 3 h

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (3598 g, 11.89 mol) was dissolved in NMP (11.108 kg) and cooled to about −3° C. A 1 M solution of NaHMDS (11.919 kg, 1.1 eq.) was added over a period of 80 minutes maintaining the temperature below 4° C. Iodomethane (1.858 kg) was added over a period of 10 minutes maintaining the temperature below 35° C. The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred for 3 hours. A 1 M solution of NaHMDS (1.2 kg) was added at 23° C. followed by iodomethane (0.188 kg). The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred overnight. The temperature was adjusted to 10° C., concentrated aqueous hydrochloric acid (6.42 L), the THF was removed by distillation at reduced pressure, the temperature was adjusted to 20° C., and water (53.3 kg) was slowly added over about 60 minutes maintaining the temperature at about 23 to 25° C. The temperature was adjusted to about 10° followed by stirring overnight. The reaction mixture was filtered, the filter cake was washed with isopropyl alcohol/water (1:1, 2×2 L), and dried in by a stream of nitrogen. The filter cake was dissolved in isopropyl alcohol (4.17 kg) at 76° C., water (20.70 kg) was slowly added over about 85 minutes maintaining the temperature at about 73 to 76° C., after 20 minutes cooled to about 11° over about 3 hours and stir overnight. Collect the solid by filtration, rinse with isopropyl alcohol/water (1:1, 2×1.7 L), and dry under a stream of nitrogen, followed by drying in an oven for 4 days to give 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=C[CH:21]=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:8](=[O:9])[CH3:21])[CH:7]=1
Reactant: OCc1cc(Br)ccc1F
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
5-Bromo-2-fluoro-phenyl-methanol (50.0 g, 228 mmol) along with 300 mL DCM was charged into 2 liter round bottom flask. Crushed pyridinium dichromate (171.0 g, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20° C. The resulting reaction mixture was filtered through Celite and washed with ether (500 mL×3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica gel pad (3 inch in length) with 10% EtOAc in hexane. The resulting product (42.0 g, yield=84%) was used in the following step.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].CC(C)([O-])C.[K+].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].C(OCC)(=O)C>CN(C)P(N(C)C)(N(C)C)=O>[C:33]1(=[O:42])[N:32]([CH2:31][CH2:30][CH2:29][O:4][C:3]2[CH:2]=[CH:1][C:17]3[CH2:16][C@H:15]4[N:18]([CH3:19])[CH2:20][CH2:21][C@:7]56[C:6]=3[C:5]=2[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]46)[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 25.0 g (87.7 mmol) of morphine in 350 ml of hexamethylphosphoramide was cooled in an ice-water bath and 10.3 g (92.0 mmol) of potassium tertiary butoxide was added through a Gooch tube over a period of 10 minutes. After stirring at room temperature for 0.5 hr, 23.5 g (87.7 mmol) of N-(3-bromopropyl)-phthalimide was added and stirring was continued at this temperature for 21 hrs. The reaction mixture was poured into 500 ml of ice-water and then 500 ml of ethyl acetate was added. The organic phase was separated and the aqueous solution was extracted with 500 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water (3 × 250 ml), 2 N sodium hydroxide, and with water (3 × 300 ml). After drying, the solvent was removed in vacuo to give 31.0 g of crude product, which after recrystallization from isopropanol--ether, yielded pure 3-(3-phthalimidopropoxy)-7,8-didehydro-4,5 α-epoxy-17-methylmorphinan-6 α-ol, m.p. 121°-123°, [α]D25 -76.63° (c 1.03, MeOH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].[CH2:22](OCC)[CH3:23]>COCCOC.O>[CH:22]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15])=[CH2:23]
Reactant: COc1ccc2ncc(C#N)c(Cl)c2n1
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1c(C#N)cnc2ccc(OC)nc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-chloro-6-(methyloxy)-1,5-naphthyridine-3-carbonitrile (280 mg, 1.28 mmol), potassium carbonate (885 mg, 6.4 mmole), tetrakis-triphenylphosphine (30 mg, 0.026 mmole) in DME/H2O (20 mL, 3:1) was added 2,4,6-trivinylcycloborane-pyridine complex (154 mg, 0.64 mmole). After stirring for 1 h at 90° C., another batch of tetrakis-triphenylphosphine (30 mg, 0.026 mmol) was added. After refluxing for another 1.5 h, the mixture contents were cooled down to room temperature and extrated with diethyl ether. The ether fractions were combined, concentrated and purified by column chromatography (silica, 0-10% ethyl acetate in hexane) to give the title compound as a light yellow solid (176 mg, 65%): LC/MS (ES) m/e 212 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[N:20][C:21]#[N:22])OC2C=CC=CC=2)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3].[F:23][C:24]1[CH:25]=[C:26]([C:30]2([NH2:34])[CH2:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C(O)(C)C>[N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:20][C:21]#[N:22])=[N:34][C:30]2([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)[CH2:33][CH2:32][CH2:31]2)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: NC1(c2cccc(F)c2)CCC1
Reactant: N#CN=C(Nc1cc(I)cc(N=[N+]=[N-])c1)Oc1ccccc1
Solvent: CC(C)O
Product: N#CNC(=NC1(c2cccc(F)c2)CCC1)Nc1cc(I)cc(N=[N+]=[N-])c1
Temperature: 82 °C
Yield: 46.6 %

Procedure:
Step B-2. To a stirred suspension of N-(3-azido-5-iodophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1, 472 mg 1.16 mmol) in isopropanol was added 1-(3-fluorophenyl)cyclobutanamine (227 mg, 1.40 mmol). The reaction mixture was heated in a sealed tube at 82° C. overnight. The cooled reaction mixture was concentrated. The residue was purified by medium pressure liquid chromatography using 30% ethyl acetate in hexane as the eluent to afford 0.257 g of N-(3-azido-5-iodophenyl)-N'-cyano-N"-[1-(3-fluorophenyl)cyclobutyl]guanidine. (B-2). Mp=171°-173° C. (dec). IR (mull) 3195, 3135, 3078, 3002, 2953, 2925, 2854, 2188, 2110, 1614, 1608, 1587, 1573, 1542, 1448, 1440, 1430, 1365, 1309, 1292, 1245, 1221, 1162, 1041, 874 cm-1 ; 1H NMR (CDCl3) δ7.42 (m, 1 H), 7.26 (m, 2 H), 7.17 (m, 2 H), 7.06 (m, 1 H), 6.78 (m, 1 H), 2.59 (m, 4 H), 2.15 (m, 1 H), 2.00 (m, 1 H), 1.61 2, 2 H); 13C NMR (CDCl3) δ156.4, 138.0, 131.3, 124.9, 120.6, 116.3, 114.7, 114.4, 112.8, 112.5, 94.9, 59.6, 34.7, 14.8; Mass Spec (FAB) m/z 476 (M+1), 448, 434, 421, 350, 328, 300, 273, 216, 173, 149 (base). Exact mass calculated for C18H16FIN7 : 476.0498. Found: 476.0514. Analysis calculated for C18H15FIN7 : C, 45.49; H, 3.18; N, 20.63. Found: C, 45.23; H, 3.16; N, 20.37.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[N:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[N:18][C:19]=1[C:23]1[CH:27]=[CH:26][O:25][C:24]=1[CH3:28]
Reactant: Cc1occc1-c1cncc(N2C[C@@H](C)O[C@@H](C)C2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)cnc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (272 mg, 1.529 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[6-(2-methyl-3-furanyl)-2-pyrazinyl]morpholine (418 mg, 1.529 mmol) in chloroform (13 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS shows desired product can be seen and no starting material left, so reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (50 mL), brine (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜5 mL) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (210 mg, 0.566 mmol, 37.0% yield). LC/MS [M+H]+=352/354.
Reaction SMILES: N1C=CC(C2[C:8](C3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=[N:9][NH:10]C=2)=CC=1.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44](=O)[CH2:45][C:46]2[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=2)=[C:40]([F:53])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:45]([C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)=[CH:8][NH:9][N:10]=2)=[C:40]([F:53])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F
Reactant: c1ccc2nc(COc3ccc(-c4n[nH]cc4-c4ccncc4)cc3)ccc2c1
Product: Fc1cc(OCc2ccccc2)ccc1-c1n[nH]cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[4-(4-Pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin-4-yl-ethanone provided the title compound. MS: (M+H m/z=346.3).
Reaction SMILES: [C:1]12([CH3:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[OH:10].[CH2:12]([OH:14])[CH3:13]>>[C:1]12([CH3:11])[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2([CH2:13][CH2:12][OH:14])[OH:10]
Reactant: CCO
Reactant: CC1(C)C2CCC1(C)C(O)C2
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2

Procedure:
Briefly described, the present invention pertains to a process for the preparation of a pharmaceutical liquid composition for orally administrating to patients such as infants, children, and critical patients, which comprises the steps of (a) extracting a first microparticle mixture of Dioscoreae rhizoma, Glycyrrhizae radix, Ginseng radix, Typhae pollen, Massa medicata fermentata, Sojae germinatum semen, Cinnamomi cortex, Paeoniae radix, Liriope tuber, Scutellariae radix, Angelicae gigantis radix, Ledebouriellae radix, Atractylodis rhizoma alba, Bupleuri radix, Platycodi radix, Armeniacae semen, hoelen, Cnidii rhizoma, Antellopis cornu, Ampelopsis radix, and Zingiberis rhizoma with water to provide a first extract and filtering the first extract to provide a first filtrate, (b) grinding Bezoar bovis and moschus and passing each ground powder to produce a Bezoar bovis powder and a Moschus powder, respectively, (c) solving Borneol with ethanol to produce a Borneol-ethanol solution, (d) solving Gelatin with warm water to produce a Gelatin solution, and (3) combining the first filtrate, the Bezoar bovis and moschus powders, the Borneol-ethanol solution, and the Gelating solution.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1ccccc1Br
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2Br)oc1C
Yield: 41.3 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (1.00 g, 10.4 mmol), commercial 2-bromobenzylbromide (2.60 g, 10.4 mmol) and 1.6M n-BuLi/hexanes (4.16 mL, 10.4 mmol) in THF. Purification on Biotage KP-Sil eluting with 100% pet. ether gave 1.14 g (41%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.84 (s, 3 H), 2.11 (s, 3 H), 3.96 (s, 2 H), 5.81 (s, 1 H), 7.19 (dt, 1 H), 7.26-7.37 (m, 2 H), 7.60 (dd, 1 H).
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]1(OB(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: OB(O)Oc1ccccc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 33.9 %

Procedure:
Scheme VI, Step A′: Into a 10 mL single neck flask was placed [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (113 mg, 0.29 mmol, prepared in example 1), phenyl boric acid (54 mg, 0.44 mmol), potassium carbonate (61 mg, 0.44 mmol), and tetrakis(triphenyl phosphine)Pd(0) (17 mg, 0.02 mmol) in a mixture of dioxane/water (3:1, 7 mL). The mixture was then heated at 100° C. with stirring for 18 hours. The reaction was then cooled to room temperature and poured into H2O. The mixture was extracted with EtOAc and the organic layer was washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via radial chromatography (Chromatotron, Harrison Research Inc., 840 Moana Court, Palo Alto, Calif. 94306) using a 2000 micron rotor (silica gel) and eluting with a solvent of Hexane/EtOAc 4:1 to provide the title compound (33 mg, 34%) as a slowly crystallizing tan oil. Ion spray M.S. 335 (M*+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14](O)=[O:15]>O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14]2=[O:15]
Reactant: COc1cccc(CC(CC(=O)O)c2ccccc2)c1OC
Solvent: O
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Temperature: 100 °C
Yield: 80.6 %

Procedure:
4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (37 g, 123 mmol), from Step 5, was added dropwise to 200 g of polyphosphoric acid heated to 100° C. The resultant mixture was stirred and heated at 100° C. for 0.25 h. A mixture of 100 g of ice and 200 mL of water was added to the reaction mixture. The precipitate which formed was filtered, washed with 3×75 mL of water and dissolved in 300 mL of methylene chloride. The methylene chloride solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give 28 g (81% yield) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, m.p. 127-128° C. 1H NMR (CDCl3) delta 2.75-3.0 (m, 3H), 3.3-3.5 (m, 2H), 3.8 (s, 3H), 3.95 (s, 3H), 6.93 (d, 1H), 7.25-7.4 (m, 5H), 7.9 (d, 1H).