Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[F:17])([CH3:4])([CH3:3])[CH3:2].C(OC(N(C1C=C([N+]([O-])=O)C=CC=1F)C(OC(C)(C)C)=O)=O)(C)(C)C.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of the above-mentioned crude product of a mixture of tert-butyl(2-fluoro-5-nitrophenyl)carbamate and di-tert-butyl(2-fluoro-5-nitrophenyl)imidodicarbonate in ethanol (600 mL)/tetrahydrofuran (60 mL) was added 10% palladium-carbon (12.0 g), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 24 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in methanol (200 mL)/tetrahydrofuran (50 mL) was added potassium carbonate (25.4 g, 184 mmol), and the mixture was stirred at 60° C. for 4 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added water (200 mL), and the mixture was extracted with ethyl acetate (300 mL, 100 mL). The combined organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (26.4 g, 63%) as pale-brown crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:50])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=2)[CH:41]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=5)[C:39]([F:50])=[CH:38][CH:37]=4)=[O:27])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (446 mg, 1 mmol) in DMF (70 mL) was added [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (230 mg, 1 mmol), PyBOP (570 mg, 1.1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) and the mixture was stirred at ambient temperature for 16 h. Additional PyBOP (518 mg, 1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) were added and the mixture stirred for an additional 2 h. The mixture was then concentrated to dryness and the residue was treated with water (400 mL) and extracted with dichloromethane (2×200 mL). The combined organics were dried (hydrophobic frit) and concentrated in vacuo and the resulting yellow oil was subjected to purification by flash chromatography (100 g silica cartridge, gradient elution from 0-100% ethyl acetate/cyclohexane) to afford 650 mg of the title compound. LC-MS m/z 665 (M+H)+, 0.98 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccccc1F
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1ccccc1F

Procedure:
Prepared by Procedure U and Scheme AK using 2-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)(=O)C>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
The 5′-O—[N-(aminoacyl)sulfamoyl]adenosine inhibitor Phe-SA (FIG. 19b) was synthesized as follows: to a solution of alcohol (7 g, 17.03 mmol, 1.0 eq) in DMAC (70 mL) at 0° C. was added DIEA (10.62 mL, 59.61 mmol, 4.0 eq) and sulfamoyl chloride (4 eq) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (4×50 mL). The organic layer was dried over MgSO4, evaporated and purified by column chromatography (DCM to 20% MeOH in DCM) to give the activated sulfamate (4.5 g, 9.18 mmol, 54% yield) To a solution of sulfamate (2.0 g, 4.07 mmole, 1 eq), DCC (0.841 g, 4.07 mmol, 1 eq), DMAP (050 g, 4.07 mmol, 1.0 eq) in DCM (45 mL) was added Boc-Phe-OH (1.1 g, 4.07 mmol, 1 eq) and the reaction mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with ethyl acetate (450 mL), washed with saturated aqueous NaHCO3, water, brine, dried over MgSO4, and evaporated. The crude product was dissolved in MeOH/n-butylamine (30 mL/30 mL) and stirred at room temperature for 3 h. The solvents were evaporated and the crude product was purified by flash chromatography (EtOAc to 10% MeOH/EtOAc) to give the Phe-SA inhibitor (0.90 g, 1.4 mmol, 35% yield)
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(CBr)CC1.N1C=CC=NC=1SC1SC(N)=NC=1>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: Nc1ncc(Sc2ncccn2)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-fluoroindole, R5X=cyclopropyl-methylbromide; NH2A=5-(pyrimidin-2-ylsulfanyl)-thiazole-2-ylamine
Reaction SMILES: Br[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[N:37]([CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:38]=[N-:39]
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C

Procedure:
A solution of 17.5 g of 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester (Z)-O-(2-bromoethyl) oxime and 5 g of sodium azide in 200 ml of N,N-dimethylformamide was stirred at 50° C. for 15 hours. The reaction solution was cooled to 20° C. and partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate and the solvent was removed in a vacuum. Crude 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester (Z)-O-(2-azido-ethyl) oxime was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)C)(=O)[CH3:14].[OH-].[Na+]>Cl>[CH3:13][C:14]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccccc2c1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cnc3ccccc3c2s1
Reaction time: 1 h

Procedure:
A mixture of 17.62 g (0.1 mole) of 3-amino-4-mercapto-quinoline and 70 ml of acetic anhydride is heated slowly to the boiling point and thereafter heated to boiling for one hour and a half. The reaction mixture is cooled and 600 ml of 1% hydrochloric acid are added dropwise under vigorous stirring. The homogenous solution is made alkaline with a sodium hydroxide solution and the precipitated base is extracted three times with 100 ml of benzene each. The united benzene extracts are clarified, dried and evaporated in vacuo. Thus 2-methyl-thiazolo[4,5-c]quinoline is obtained, m.p.: 99°-100° C. (after recrystallization from a mixture of methanol and water).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Oc1ccc(C=Cc2ccncc2)cc1

Procedure:
By the reaction of 20.0 g of γ-picolin and 26.2 g of p-hydroxybenzaldehyde in 65.8 g of acetic anhydride, there was obtained 4-[2-(4-hydroxyphenyl)-ethenyl]-pyridine. In 10 cm3 of N,N-dimethylacetamide, 2 g of the reaction product was dissolved and 1.23 g of triethylamine was further added thereto. This mixture was ice cooled and 1.34 g of methacrylic acid chloride was dropwise added thereto. After the reaction was completed, water was added to deposit crystals, which were separated by filtration. The separated crystals were recrystallized via a mixed solvent of ethyl acetate and hexane, to afford 2.16 g (80% in yield) of 4-[2-(4-methacryloyloxyphenyl)-ethenyl]-pyridine. The melting point of the crystals was 156° to 158° C.
Reaction SMILES: C(=O)(OC)OC.[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](=O)([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:15]C>>[C:14](=[O:15])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)Oc1ccccc1
Solvent: COC(=O)OC
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
An apparatus comprising two continuous multi-stage distillation columns as shown in FIG. 3 was employed. Reaction was performed by continuously feeding in a liquid form a mixture of dimethyl carbonate, phenol and Catalyst A to first continuous multi-stage distillation column 1' at a position 1 m below top 17 thereof, which column was comprised of a packed column of 4 m in height and 3 inches in diameter and packed with stainless steel-made Dixon packing (diameter: about 6 mm), from material feeding pipe 2 through conduit 4, preheater 5 and conduit 6, thereby allowing the mixture to flow down the inside of the first continuous multi-stage distillation column. The thermal energy necessary for reaction and distillation was supplied by circulating the column bottom liquid through conduits 8 and 9, reboiler 10 where heating was effected and conduit 11. The gas continuously distilled from column top 17 was led through conduit 12 to condenser 13 where the gas was condensed. A portion of the resultant condensate was recycled to first continuous multi-stage distillation column 1, through conduits 14 and 15 and the rest of the condensate was continuously withdrawn through conduit 16. From the withdrawn condensate, a low boiling point component containing methanol which was a low boiling point reaction product was obtained. A high boiling point component containing the catalyst component and methyl phenyl carbonate was continuously withdrawn from column bottom 18 through conduits 8 and 19.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([C@@H:16]([C@H:18]([C:20]([O:22][CH3:23])=[O:21])[OH:19])O)([O:14][CH3:15])=[O:13]>>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:2]2[O:19][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[C@H:16]([C:12]([O:14][CH3:15])=[O:13])[O:1]2)[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Reactant: COc1cc(C=O)ccc1O
Product: COC(=O)[C@@H]1OC(c2ccc(O)c(OC)c2)O[C@H]1C(=O)OC

Procedure:
In a fashion similar to that described for Example 3, vanillin and dimethyl L-tartrate were condensed to provide (4R, 5R)-2-(3-methoxy-4-hydroxy-phenyl)-4,5-dicarbomethoxy-1,3-dioxolane, mp 88°-90° C., [α]D25 -35.1° (c,0.1,methanol). 1H-NMR (CDCl3)δ7.20 (1H,d,J=1. 8 Hz), 7.06 (1H,dd,J=1.8 Hz and 8.2 Hz), 6.19 (1H,d,J=8.2 Hz), 6.08 (1H,s), 5.82 (1H, s), 4.96 (1H,d,J=3.8 Hz), 4.85 (1H,d,J=3.8 Hz), 3.91 (3H,s), 3.87 (3H,s), 3.84 (3H,s). IR (film) 3450, 1750, 1600, 1510, 1460, 1430 cm-1. Ms m/e (% abundance) 313(2), 312(12), 253(40), 168(84), 151(100), 124(22), 109(14), 59(18).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:47])[N:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38](C)(C)[O:39][SiH2]C(C)(C)C)[CH:32]=1)[CH2:26][CH:27]([F:29])[F:28])([CH3:22])([CH3:21])[CH3:20]>C1COCC1.CCOC(C)=O>[C:19]([O:23][C:24](=[O:47])[N:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][OH:39])[CH:32]=1)[CH2:26][CH:27]([F:29])[F:28])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)CC(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CO)c1)CC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
TBAF (1M in THF, 9.57 mL, 9.57 mmol) was added dropwise to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (2.15 g, 4.78 mmol) in THF (48 mL) at 0° C. The mixture was was stirred for 1 h while warming up to rt. The mixture was diluted with EtOAc, and the resulting mixture was washed with aq. sat. NH4Cl (2×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 30:70) yielded the title compound (591 mg, 37%). LC-MS: tR=0.97 min; ES+: 336.09.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])[CH3:2].C(OC(=O)C)(=O)C.[N+:23]([O-])([OH:25])=[O:24]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([N+:23]([O-:25])=[O:24])[CH:13]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)OC)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of methyl 4-ethoxy-3-methoxybenzoate (7.12 g, 33.9 mmol) and acetic anhydride (40 mL) in acetic acid (40 mL) at room temperature was dropped fume nitric acid (90%, 3.15 g). After stirring at room temperature for 15 minutes, it was heated at 50° C. for 1 hour. The reaction mixture was poured into ice and a solid was formed. It was filtered, washed with water, and dried under vacuum with P2O5 to give methyl 4-ethoxy-5-methoxy-2-nitrobenzoate as white solid (8.392 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.07 (s, 1H), 4.19 (q, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 1.52 (t, 3H); LC-MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1ccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (100 mL), 1-methyl-1H-pyrazol-3-amine (970 mg, 10.0 mmol), 3,5-dibromo-1-methylpyridin-2-(1H)-one (2.9 g, 11 mmol), and cesium carbonate (6.5 g, 20.0 mmol). After bubbling nitrogen through the suspension for 10 minutes, tris(dibenzylideneacetone)dipalladium(0) (457 mg, 0.50 mmol) and Xantphos (587 mg, 1.0 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 2 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×50 mL) and the combined organic filtrate was concentrated. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 290a as a yellow solid (900 mg, 32%). MS-ESI: [M+H]+ 283.1
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:24]=[N:25][N:26](C(C)(C4C=CC=CC=4)C)[N:27]=3)=[CH:13][CH:12]=2)[C:8]([CH2:37][OH:38])=[C:7]([Cl:39])[N:6]=1)[CH2:2][CH2:3][CH3:4]>ClCCl>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:37][OH:38])=[C:7]([Cl:39])[N:6]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Yield: 92.2 %

Procedure:
10 g (0.02 moles) of (2-butyl-5-chloro-3-{2′-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol are dissolved in 50 ml of dichloromethane and gaseous HCl is bubbled at a temperature of 0-10° C. After 2 h the reaction mixture is poured into a solution of 55 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70° C., thereby obtaining 7.8 g of losartan.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
reacting 2-nitro-4-tertbutylanisole with an acid mixture of nitric acid, sulfuric acid and oleum to produce 2,6-dinitro-4-tertbutylanisole; and
Reaction SMILES: [CH2:1]=[C:2]([CH:10]([OH:15])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Na+].C(O)(=O)C>[CH2:1]=[C:2]([CH:10]([O:15][C:16](=[O:18])[CH3:17])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OCCCC)C(O)C(Cl)(Cl)Cl
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=C(C(=O)OCCCC)C(OC(C)=O)C(Cl)(Cl)Cl
Temperature: 120 °C
Yield: 91.4 %

Procedure:
To 1173.0 g of butyl 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate (91% pure) charged in a 2-liter, 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, and a condenser were added 520.0 g of acetic anhydride and 7.0 g of sodium acetate. The reaction mixture was heated at 120° C. for three hours. Unreacted acetic to anhydride and formed acetic acid were stripped off under vacuum at <80° C./0.6 mm Hg. After cooling to room temperature, the solid sodium acetate that had settled to the bottom of the flask was separated. 1236.1 g of acetylated product was obtained, 91.3% purity (GC analysis), 91.4% yield. The product structure was confirmed by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[Mg].II.FC1C=C([Mg]Br)C=C(F)C=1F.[C:25]([O:29][C:30]([N:32]1[C:37](=[O:38])[CH2:36][O:35][CH2:34][C@@H:33]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.O1CCCC1.C(OCC)C>[C:25]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([CH2:39][O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:34][O:35][CH2:36][C:37](=[O:38])[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@@H]1COCc1ccccc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Fc1cc([Mg]Br)cc(F)c1F
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1cc(F)c(F)c(F)c1)COCc1ccccc1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 1-bromo-3,4,5-trifluorobenzene (2 mL) was added to a diethyl ether (200 mL) suspension of magnesium (6.87 g) and iodine (trace amount) and the resultant was heated by heatgun until reaction started. 1-bromo-3,4,5-trifluorobenzene (31.7 mL) was further added dropwise. Once reflux has stopped, stirring was continued for 1.5 hours at room temperature. Under a nitrogen atmosphere, previously prepared 3,4,5-trifluorophenyl magnesium bromide was added dropwise at −35° C. or less into a tetrahydrofuran (800 mL) solution of (S)-3-benzyloxymethyl-5-oxomorpholine-4-carboxylic acid t-butyl ester (82.8 g) that was cooled to −40° C. Stirring was continued for 2 hours at −40° C., saturated ammonium chloride aqueous solution (200 mL) and water (300 mL) were added, and the temperature was raised to room temperature. Toluene (500 mL) was added, and the organic layer was partitioned. The organic layer was washed with brine. The aqueous layers were combined, ethyl acetate (400 mL) was added, and the organic layer was partitioned. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum. The residue was purified with silica gel column chromatography (heptane/ethyl acetate 9/1→8/2→3/1), and the title compound was obtained (82.6 g). The physical property values are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1C(=O)CCC1.O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 51.6 %

Procedure:
4-Hydroxybenzaldehyde (15 g, 122 mmol) was dissolved in 150 ml of NMP. 6-Chlorohexanol (20.16 g 146 mmol), anhydrous potassium carbonate (20.36 g, 146 mmol) and a catalytic amount of potassium iodide were added. The batch was stirred at 90 C for 24 hours. Water was added to the cooled solution, which was subsequently extracted with 3×100 mls of ethyl acetate. The combined organics were washed with 5% KOH (2×100 mls), brine solution and then dried over magnesium sulfate. The concentrated product was then recrystallized from a 1:1 mixture of ethyl acetate/hexane to give 14 g of an off-white solid.