Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[CH:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7][C:6]=2[CH:22]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:15]([CH:9]1[CH2:8][CH2:7][C:6]2[CH:22]=[C:2]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:3]([O:23][CH3:24])=[CH:4][C:5]=2[N:11]([CH2:12][CH3:13])[C:10]1=[O:14])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C1CNCCN1
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2cc(Br)c(OC)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2cc(N3CCNCC3)c(OC)cc21
Temperature: 80 °C
Yield: 16.4 %

Procedure:
An oven-dried flask, charged with 7-bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (48 mg, 0.121 mmol), piperazine (12.64 mg, 0.145 mmol), Pd(OAc)2 (2.72 mg, 0.0121 mmol, 10 mole), BINAP (11.65 mg, 0.0182 mmol) was purged with argon for 5 min. After addition of anhydrous toluene (1 mL) through a syringe followed by sodium tert-butoxide (16.78 mg, 0.169 mmol) in one portion, the flask was purged with argon, vigorously stirred and heated at 80° C. for 22 hrs. The course of the reaction was monitored by TLC. The reaction mixture was diluted with DCM (20 mL), percolated through a short column of Celite and evaporated to dryness. Purification of a crude product using preparative silica TLC developed with MeOH/DCM (1:4) provided the desired compound (8.0 mg, 16%) as a white crystalline product.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C([O-])=O.[NH4+].[Cl-].[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 95.5 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (30 g, 0.11 mols), ammonium formate (13.3 g, 0.21 mols), lithium chloride (8.9 g, 0.21 mols) and methanol (180 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (6 g) (as metal palladium; 1 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. With stirring, the reaction liquid was reacted at the same temperature for 4 hours. Water (10 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (30 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (20 g, yield 100% by mass).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH:27]([CH3:29])[CH3:28])=[C:20]([C:22](OCC)=[O:23])[N:21]=4)=[C:13]([NH:30][CH:31]([CH3:33])[CH3:32])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH:27]([CH3:29])[CH3:28])=[C:20]([CH2:22][OH:23])[N:21]=4)=[C:13]([NH:30][CH:31]([CH3:33])[CH3:32])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(CO)c(C(C)C)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate (29) (150 mg, 0.34 mmol) in dry Tetrahydrofuran (10 mL) was added LAH (0.739 mmol) (4% in THF) at −10° C. The reaction mixture was stirred at 0° C. for 30 min, reaction temperature was then brought to room temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched by using ice flakes (until the H2 gas evolution ceased), followed by 1N NaOH solution, filtered through celite, precipitate was washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuum to give crude compound. The crude material was purified by flash column chromatography using silica gel and ethyl acetate/hexane as eluent to provide (2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazol-4-yl)methanol. 1H NMR: 400 MHz, DMSO-d6: δ 1.28-1.30 (m, 12H), 3.68-3.73 (m, 1H), 4.38-4.39 (m, 2H), 5.03-5.03 (m, 1H), 6.15 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.11 (d, J=6.80 Hz, 1H), 8.54 (s, 1H), 8.74 (d, J=1.60 Hz, 1H), 9.15 (s, 1H), 9.30 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.703 min; LCMS (ES-API), m/z 424.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.663 min; Purity: 99.2%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[N:6][C:7]=1[C:8]([CH3:10])=[CH2:9].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[N:6][C:7]=1[CH:8]([CH3:9])[CH3:10]
Reactant: [H][H]
Reactant: C=C(C)c1nc(N)ccc1F
Agent: [Pd]
Solvent: CO
Product: CC(C)c1nc(N)ccc1F
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of 5-fluoro-6-isopropenyl-pyridin-2-ylamine (crude from last step, 4.45 mmol) in methanol (13.5 mL) was added 10% palladium on carbon (95 mg) at room temperature. A hydrogen balloon (1 atm) was attached and the mixture was stirred overnight. After 18 h, the mixture was filtered over Celite, concentrated on to silica gel, and chromatographed (10% to 40% EtOAc in hexanes) to give 5-fluoro-6-isopropylpyridin-2-amine (470 mg, 69% over two steps). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.12 (t, J=9.2 Hz, 1H), 6.30 (dd, J=8.5, 3.0 Hz, 1H), 4.31 (br. s, 2H), 4.15 (m, 1H), 1.26 (d, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[CH3:14][Si](C)(C)Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: COc1nc(C(=O)O)ccc1C#N
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1ccc(C#N)c(OC)n1

Procedure:
5-Cyano-6-methoxypyridine-2-carboxylic acid (see above) is reacted in methanol with the help of trimethylchlorosilane to give methyl 5-cyano-6-methoxypyridine-2-carboxylate (m.p. 125°-125° C.). Subsequent hydrogenation in methanol on palladium/charcoal in the presence of hydrochloride acid gives the desired aminomethyl compound (m.p. of the hydrochloride: 224°-226° C.). By the addition of a few drops of triethanolamine, the hydrogenation solution is brought to a pH of 7 and used directly for the following reaction.
Reaction SMILES: C1(COC2C(C3N(CC4C=C[C:21]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:20][CH:19]=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46](CC3CCCCC3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC1CCCCO1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:19][CH:20]3[CH2:21][CH2:24][CH2:25][CH2:26][O:28]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: BrCC1CCCCO1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCO1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 2-bromomethyl-tetrahydro-pyran (CAS Reg. No. 34723-82-5). Brown powder (39%). MS (Turbo Spray): m/z=393.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:34][C:35]=2[CH3:36])[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3nc(-c4ccccc4)oc3C)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
After a mixture of ethyl 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (621 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2.5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (439 mg, yield: 74%). This was recrystallized from ethanol-hexane. Melting point: 126–127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:23]([CH:26]([CH3:28])[CH3:27])([O-:25])=[O:24].C(O)C.CC[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:22])[CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[C:26]([CH3:28])([N+:23]([O-:25])=[O:24])[CH3:27])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)C=Cc2ccncc2)cc(OC)c1OC
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=O)CC(c2ccncc2)C(C)(C)[N+](=O)[O-])cc(OC)c1OC

Procedure:
A solution of 40 g. of 3',4',5'-trimethoxy-3-(4-pyridyl)-acrylophenone and 24 g. of 2-nitropropane in 270 ml. of ethanol is heated at reflux with stirring under a nitrogen atmosphere. Within 1 hour there is added dropwise a sodium ethylate solution (manufactured from 1.35 g. of sodium and 27 ml. of ethanol). The reaction mixture left standing for a half hour to react further is then evaporated under reduced pressure. The residue results is taken up in methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The product which results is crystallized with chloroform ether to yield 3',4',5'-trimethoxy-4-methyl-4-nitro-3-(4-pyridyl)-valerophenone, melting point 214°-216° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]#[C:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:28])[C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=4)=[CH:13][O:14]3)=[CH:9][CH:8]=2)[CH2:2]1.FC(F)(F)C(O)=O.[CH:36](=O)[CH:37]([CH3:39])[CH3:38].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1>[CH2:36]([N:1]1[CH2:4][CH:3]([C:5]#[C:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:28])[C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=4)=[CH:13][O:14]3)=[CH:9][CH:8]=2)[CH2:2]1)[CH:37]([CH3:39])[CH3:38]
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(C#CC4CNC4)ccc3c2=O)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)CN1CC(C#Cc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(4-(7-(azetidin-3-ylethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.trifluoroacetic acid salt (75 mgs, 0.190 mmol) in 1,2-dichloroethane/tetrahydrofuran (3 mL/0.5 mL), was added isobutyraldehyde (0.03 mL, 0.285 mmol), triethylamine (0.05 mL, 0.38 mmol) and sodium triacetoxyborohydride (60 mgs, 0.285 mmol). The mixture was stirred at room temperature for 16 hours, then the reaction mixture was quenched by adding aqueous 1N sodium hydroxide, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated and washed with diethylether to give N-(4-(7-((1-isobutylazetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]#[C:18][Si](C)(C)C)[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]1.[F-].[Cs+].CN(C=O)C>CO>[C:17]([C:16]1[CH:15]=[CH:14][C:4]([CH2:5][N:6]2[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]2)=[CH:3][C:2]=1[F:1])#[CH:18]
Reactant: COC(=O)C1CN(Cc2ccc(C#C[Si](C)(C)C)c(F)c2)C1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reaction time: 2 h

Procedure:
Methyl 1-(3-fluoro-4-(2-(trimethylsilyl)ethynyl)benzyl)azetidine-3-carboxylate (20.9 g, 65 mmol), and cesium fluoride (11 g, 72 mmol), was added to DMF (50 mL). MeOH (100 mL) was added. After 2 h, MeOH was removed and the mixture was extracted with DCM and water. The organic layer is washed with brine and dried over magnesium sulfate. The solvent was removed and the material purified using Biotage (75 L, 7-100% EtOAc/hexanes) affording methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate as light yellow oil. MS (ESI) m/z: Calculated: 247.1; Observed: 248.0 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]=[CH:22][N:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 145 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A mixture of 3-benzyl-7-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.60 g, 5.85 mmol), N,N-dimethylformamide dimethyl acetal (5.6 mL, 39.6 mmol) and MgSO4 (5.0 g, 41.5 mmol) in DMF (20 mL) was sealed under nitrogen and heated at 145° C. overnight. The reaction mixture was cooled to 0° C., poured into ice water and stirred for 1 h. The solid was collected and washed with water, dried under vaccum over P2O5 to give the title compound (1.84 g, 96%): 1H NMR (CDCl3) δ 7.50 (d, 1H, J=12.56 Hz), 7.30 (m, 2H), 7.24 (m, 4H), 6.96 (d, 1H, J=4.48 Hz), 6.38 (d, 1H, J=4.68 Hz), 5.27 (s, 2H), 2.83 (s, 3H).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16](O)(=[O:20])[CH2:17][CH2:18][CH3:19].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:36][CH2:37][CH2:38][C@@H:39]([CH2:52][OH:53])[CH2:40][N:41]1[CH:49]=[N:48][C:47]2[C:46](=[O:50])[NH:45][C:44]([NH2:51])=[N:43][C:42]1=2)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:36][CH2:37][CH2:38][C@@H:39]([CH2:52][O:53][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:40][N:41]1[CH:49]=[N:48][C:47]2[C:46](=[O:50])[NH:45][C:44]([NH2:51])=[N:43][C:42]1=2)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 34.4 %

Procedure:
DCC (110 mg, 0.53 mmol) was dissolved in dichloromethane (10 ml) and butyric acid (82 mg, 0.93 mmol) was added. After 4 hours at room temperature the mixture was filtered and the filtrate was evaporated. The residue was dissolved in pyridine (5 ml) and (R)-9-[4-(N-tert-Butoxycarbonyl-L-valyloxy)-2-hydroxymethylbutyl]guanine (200 mg, 0.44 mmol) (Example 1, step a) was added. The mixture was stirred for 120 hours at room temperature. According to TLC the reaction was incomplete and more anhydride was made using the procedure above. This anhydride was added and the mixture was stirred for an additional 20 hours. The reaction mixture was evaporated and chromatographed first on silica gel and then on aluminium oxide, in both cases eluted with dichloromethane/methanol to give 79 mg of the intermediate product.
Reaction SMILES: COS([O-])(=O)=O.CN(C)[C:9]1[CH2:13][CH2:12][CH2:11][N+:10]=1[CH3:14].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].O>C(O)(C)(C)C.CN(C)C=O>[CH3:14][N:10]1[CH2:11][CH2:12][CH2:13][C:9]1=[CH:25][C:22]1[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CN(C)C1=[N+](C)CCC1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: COS(=O)(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)(C)O
Product: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1
Yield: 22.8 %

Procedure:
Add a solution of 2.35 g of potassium tert. butylate in 15 ml of tert. butanol and 10 ml of dimethylformamide dropwise at 130° to a mixture of 5.0 g of 2-dimethylamino-1-methyl-1-pyrrolinium methylsulfate and 2.2 g of 4-nitrotoluene in 15 ml of dimethylformamide. Stir the thus-prepared reaction mixture at this temperature for 2 hours. Allow the mixture to cool, add water to it and then extract it several times with chloroform. Combine and then concentrate the chloroform extracts. Distil off a slight excess of 4-nitrotoluene under a high vacuum and recrystallize the produced residue from 10 ml of ethanol to obtain 0.8 g of title compound.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][CH:21]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: FC(F)(F)c1cccc(C=C2c3ccccc3CCc3ccccc32)c1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 3-(trifluoromethyl)phenyl boronic acid (0.33 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. Analysis for C23H17F3: Calcd: C, 78.84 H. 4.89; Found: C, 79.03.H, 5.03. HPLC (ISO80-10M)) t=16.30 min (98%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([NH2:28])[CH3:27])[CH:22]=[CH:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:28][CH:26]([C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)[CH3:27])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CCl
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 4.24 g of 3-chloro-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid ethyl ester, 2.85 g of 1-(3,4-dichlorophenyl)ethylamine, 1.95 g of Hunig base and 15 ml of ethanol is heated at reflux for 4 days. After cooling to room temperature and removal of the solvent under reduced pressure, the reaction mixture is partitioned between dichloro-methane and water, dried over sodium sulfate and again concentrated to dryness by evaporation. Chromatography on silica gel yields 3-{N-[1-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester, [α]20D =-1.8°±0.9° (c=1.079 in chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.[H-].[Na+].[CH3:18]I.O>C1COCC1>[CH3:18][O:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:12]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]=2[O:9]1
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)OC(CO)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1Cc2cc(C)cc([N+](=O)[O-])c2O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5-methyl-7-nitro-2,3-dihydrobenzofuran-2-yl)methanol (0.70 g, 3.3 mmol) in THF was cooled to 0° C. NaH was added to the mixture at 0° C. It was stirred for 15 min at 0° C. MeI was added dropwise to the mixture at 0° C. It was stirred for 0.5 h at 0° C. The mixture was poured into water (20 mL), extracted with EtOAc (40 mL), washed with water, brine, dried and concentrated to give the title compound (8a) as a yellow oil. MS-ESI (m/z): 224 (M+1)+.
Reaction SMILES: C1(C([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[CH:24]([C:29]4[N:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1>CC(C)=O>[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[CH:24]([C:29]3[N:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12.[CH3:52][C:42]1[CH:47]=[CH:46][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: CCOC(=O)n1nnnc1C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)n1nnnc1C1N2C(=O)C(N)[C@H]2SC1(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 554 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam in 2 ml. of acetone is added a solution of 190 mg. of p-toluenesulfonic acid monohydrate in 1 ml. of acetone. Stirring is continued for a further 3 hours, and then the acetone is removed by evaporation in vacuo. The residue is slurried in ether, filtered and dried, to give the title compound as its p-toluenesulfonate salt.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1.O>CN(C)C=O>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:21]=2)=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(-c2coc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (0.39 g) and 4-trifluoromethoxybenzamide (0.39 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at 140° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow solid (70 mg).