Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10]([C:11]#[N:12])=[C:9]([F:13])[C:8]([F:14])=[C:7](F)[C:6]=1[F:16]>CO>[CH3:1][O:2][C:7]1[C:6]([F:16])=[C:5]([F:4])[C:10]([C:11]#[N:12])=[C:9]([F:13])[C:8]=1[F:14]
Reactant: C[O-]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: CO
Product: COc1c(F)c(F)c(C#N)c(F)c1F
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 44.8 g (0.83 mole) of sodium methoxide in 1.6 liters of methanol was added dropwise at room temperature to a solution of 160.0 g (0.83 mole) of pentafluorobenzonitrile (XVIII) in 2.5 liters of methanol, whilst stirring. When the addition was complete, the mixture was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was shaken with a mixture of water and toluene. The toluene layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residual solid was washed with hexane to afford 160.7 g of 4-methoxy-2,3,5,6-tetrafluorobenzonitrile (XIX) as colorless needles.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[Si:15]([O:14][CH2:13][CH2:12][O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a solution of the product of Example 5B (670 mg, 2.18 mmol) dissolved in anhydrous THF (22 mL) was added a solution of LAH (1.0 M solution in THF, 2.18 mL, 2.18 mmol) dropwise. After completion of addition the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil (587 mg, 1.98 mmol), which was used in the next step without any further purification (91% yield).
Reaction SMILES: [C-]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:14]S([O-])(=O)=O.O>CN(C)C=O>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][C:14]#[N:2]
Reactant: [C-]#N
Reactant: CCCCC(CCS(=O)(=O)[O-])c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC#N)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a suspension of 11.3 g (0.23 mole) of sodium cyanide in 100 ml of dry dimethyl formamide (DMF) is added dropwise a solution of 50 g (0.154 mole) of 2-(2,4-dichlorophenyl)-hexylmethane sulfonate in 50 ml of DMF. The reaction mixture is stirred at 70° overnight. It is then poured into 500 ml of water and extracted with ether. The combined ether extracts are washed with water, then saturated saline solution and finally dried over magnesium sulfate. Solvent is evaporated under reduced pressure to give 37 g of crude product which is further purified by vacuum distillation (107.5°-110°/0.05 mm) to give 33.9 g (86%) of expected product.
Reaction SMILES: [Na].[H-].COCCO[Al+]OCCOC.C1(C)C=CC=CC=1.CS([N:25]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:27]2([CH2:32][CH2:31][N:30]([C:33](OCC3C=CC=CC=3)=O)[CH2:29][CH2:28]2)[CH2:26]1)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:33][N:30]1[CH2:29][CH2:28][C:27]2([C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[NH:25][CH2:26]2)[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)N1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC2(CC1)CNc1ccccc12
Temperature: 0 °C
Yield: 63.4 %

Procedure:
In a nitrogen atmosphere, 3.8 mL of 65% sodium-bis(2-methoxyethoxy)aluminium hydride-toluene solution was added to toluene (20 mL) solution of 1 g of benzyl 1-methanesulfonyl-spiro[2,3-dihydro-1H-indole-3,4′-piperidine]-1′-carboxylate (prepared according to the method described in Tetrahedron, 1997, 53, 10983-10992), and refluxed for 3 hours. The reaction liquid was cooled to 0° C., poured into aqueous 1 M sodium hydroxide solution at that temperature, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (aqueous 1% ammonia, chloroform/methanol=5/1) to obtain 0.32 g of the entitled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:38](O)=[O:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:38]=[O:39])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1C=O
Reaction time: 0.5 h

Procedure:
A solution of 2-[3,5-dichloro-4-(4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (1 g) and hexamethylenetetraamine (0.6 g) in trifluoroacetic acid (8 mL) was stirred at 70° C. for 18 h. The trifluoroacetic acid was removed in vacuo, water added and the resulting mixture was stirred for 30 min. The residue was extracted with ethyl acetate, the organic phase washed with water, brine, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (35% acetone/hexanes) to afford the title compound of Step A as an off-white solid, 1.0 g (m.p. 184-187° C.).
Reaction SMILES: [F:1][C:2]1([CH:8]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[C:9]([F:12])([F:11])[F:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[F:1][C:2]1([CH:8]([O:13][Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:15][CH3:16])[C:9]([F:11])([F:12])[F:10])[CH2:3][CH2:4][N:5]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
4-Fluoro-4-[2,2,2-trifluoro-1-(triethylsiloxy)ethyl]-piperidine (300 mg, 0.951 mmol) was dissolved in dichloromethane (6 mL). To this, triethylamine (0.199 mL, 1.43 mmol) and methanesulfonyl chloride (0.140 mL, 1.43 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 4-fluoro-1-methanesulfonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (309 mg, yield: 83%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[S:9](=O)(=[O:12])([OH:11])[OH:10].C1(O)C=C(C)C=C(O)C=1.CC1C=C(O)C=CC=1O.CC1C=CC=C(O)C=1O.[OH-].[K+]>C(OCC)C>[C:1]1([S:9]([OH:12])(=[O:11])=[O:10])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(O)c1
Agent: Cc1cc(O)cc(O)c1
Agent: Cc1cc(O)ccc1O
Agent: Cc1cccc(O)c1O
Solvent: CCOCC
Product: Cc1cccc(O)c1S(=O)(=O)O
Reaction time: 0.67 h

Procedure:
A 500 ml three-neck flask, equipped with magnetic stirrer, addition funnel and reflux condenser, was charged with 108.0g (1.0 mole) of m-cresol. Sulfuric acid (96.5%), 147.9g was added dropwise during 25 minutes, while the temperature rose to 80°. External heating by mantle raised the temperature to 107° during 15 min. and Sample 1 was withdrawn. The sample was diluted with water, made basic with aqueous sodium hydroxide and the water was evaporated. The resultant salts, 11.0 g. were fused with 25 g. potassium hydroxide for 40 min. at 235°-330° under a nitrogen atmosphere. The mass was diluted with water, acidified with hydrochloric acid to pH 2 and extracted with four portions of 100 ml each of ether. The solvent was boiled off leaving only 0.5 g. of residue. Infrared and nuclear magnetic resonance showed it to contain 36% m-cresol, 26% diethyl ether solvent and 38% aryl carboxylic acids. There was no evidence of orcinol, methylhydroquinone and methylcatechol. Continuous liquid-liquid extraction of the aqueous phase with ether for five hours only produced 0.2 g. of additional product. A repeat fusion on ca. 25 ml of reaction mixture produced 45 g. of salts which were fused with 100 g. of potassium hydroxide for 35 min. at 350° to 360°. Work-up produced only 2.2 g. in which only m-cresol could be identified. The sulfonation resulted in the formation of substantially only m-cresolsulfonic acid isomers wherein the acid group is in ortho and/or para position relative to the hydroxyl group. The failure to obtain methylhydroquinone and/or 4-methylcatechol by fusion from the above m-cresol-sulfonic acids is not surprising in view of Barth and Senhofer's [Ber. 9, 969 (1876)] failure to fuse o- and p- phenolsulfonic acids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2cn[nH]c2c1

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting 5-bromooxindole (40 mg, 0.189 mmol) and 1H-indazole-6-carbaldehyde (30 mg, 0.208 mmol) to obtain 1.0 mg (1.6%) of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.98-7.92 (m, 2H), 7.87 (s, 1H), 7.73 (s, 1H), 7.44 (d, J=8.34 Hz, 1H), 7.39 (d, J=8.59 Hz, 1H), 6.87 (d, J=8.34 Hz, 1H); MS ESI 340.1 [M+H]+, calcd for [C16H10BrN3O+H]+ 340.01.
Reaction SMILES: [O:1]=[C:2]([O:23][CH2:24][CH:25]=[CH2:26])[CH2:3][O:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.[ClH:27]>C(OCC)(=O)C>[ClH:27].[ClH:27].[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]([NH:5][O:4][CH2:3][C:2]([O:23][CH2:24][CH:25]=[CH2:26])=[O:1])[CH2:7][NH:8]1
Reactant: C=CCOC(=O)CONC1CN(C(=O)OC(C)(C)C)Nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CONC1CNNc2ccccc21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
The 6.16 g of the product obtained in stage C are dissolved in 22 ml of ethyl acetate, and then 38 ml of a 4.3M solution of hydrogen chloride gas in ethyl acetate are added at 0° C. with stirring and under argon. The mixture is brought back to ambient temperature. After 30 min, the precipitate is filtered off, washed with ether and dried under reduced pressure. 5.63 g of the expected product (99%) are isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:18]([CH:28]=C)[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:9][CH:10]([OH:17])[C:11](=C)[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>C1(C)C=CC=CC=1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Si:21]([O:20][CH2:19][C@@H:18]1[CH:28]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:10]([OH:17])[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([C:24]([CH3:26])([CH3:27])[CH3:25])([CH3:22])[CH3:23]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(O)C(=C)C(=O)OC)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O

Procedure:
A stirred solution of methyl 4-(tert-butoxycarbonyl((S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)amino)-3-hydroxy-2-methylenebutanoate (Intermediate 100, 16 g, 37 mmol) in toluene (about 300 mL), at ambient temperature in a heat-dried flask, was thoroughly degassed with argon and placed under a nitrogen atmosphere. To this was added Hoveyda-Grubbs Catalyst 2nd Generation (460 mg, 0.74 mmol). Analysis of the mixture 3.5 hours later by LCMS and TLC (15% ethyl acetate in hexanes) indicated very high conversion of starting material to two major products. The reaction mixture was concentrated in vacuo in the presence of enough silica gel to give a free-flowing powder upon reaching dryness. Normal-phase chromatography (0-100% ethyl acetate in hexanes, 330-g column, 45 minutes) was used to isolate the two compounds; the diastereomer shown above (6.4 g, 43%, dark oil) eluted first.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[CH2:12]1)=[O:4].O.NN>CO.O>[NH2:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:12]1
Reactant: COC(=O)c1ccccc1N1CCCC(CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1ccccc1N1CCCC(CN)C1
Yield: 77.8 %

Procedure:
N-[[1-[2-(Methoxycarbonyl)phenyl]piperidin-3-yl]methyl]phthalimide (495 mg, 1.31 mmol) was dissolved in methanol (10 mL). To this solution, hydrazine monohydrate (190 μL) was added and the mixture was refluxed for 3 hours. Subsequently, the reaction mixture was diluted with water and extracted with ethylacetate. The organic layer washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 253 mg (78%) of the desired compound as an orange oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][Si:2]([CH3:12])([CH3:1])[CH3:13])=[O:18]
Reactant: C[Si](C)(C)CCc1ccccc1N
Reactant: O=C(Cl)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCc1ccccc1NC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
425 mg of 2-(2-trimethylsilylethyl)phenylamine (2.2 mmol) and 438 mg (2.0 mmol) of 2-bromo-benzoyl chloride were dissolved in 20 ml of acetonitrile, and 332 mg (2.4 mmol) of potassium carbonate were added. The reaction mixture was stirred at room temperature for 18 h, 20 ml of water were then added, the mixture was extracted with ethyl acetate and the extract was dried over sodium sulphate. Removal of the solvent and column-chromatographic purification on silica gel 60 (mobile phase: methylene chloride) gave 405 mg (54% of theory) of 2-bromo-N-[2-(2-trimethylsilyl-ethyl)phenyl]benzamide [log P (pH 2.3)=4.32].
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:25]([C:19]1([NH:18][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:26])[NH2:27]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)C1(N)CCOCC1
Product: NC(=O)C1(NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)CCOCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 4-aminotetrahydro-2H-pyran-4-carboxamide (CAN 1183378-09-7) as starting materials, MS (EI): m/e=360.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)([O-:3])=[O:2].Br[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH:26]([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C(O)=O>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>[Cl:24][C:22]1[CH:23]=[CH:18][C:19]([O:25][CH:26]([F:27])[F:28])=[C:20]([C:8]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:21]=1
Reactant: FC(F)Oc1ccc(Cl)cc1Br
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1-c1cc(Cl)ccc1OC(F)F
Temperature: 130 °C
Yield: 77.8 %

Procedure:
To a solution of 4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (preparation described in WO2011003065) (46.5 g, 191 mmol) in DMA (350 mL) was added 2-bromo-4-chloro-1-difluoromethoxybenzene (64.0 g, 248 mmol), palladium (II) acetate (2.15 g, 9.6 mmol), di-(adamantyl)-n-butylphosphine (5.0 g, 13.4 mmol), potassium carbonate (79.2 g, 573 mmol) and trimethylacetic acid (5.27 g, 51.6 mmol). The mixture was degassed with nitrogen for 10 minutes then heated at 130° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water and brine, dried (MgSO4), filtered and evaporated. The resultant crude material was purified by flash chromatography on silica eluting with 0-10% EtOAc in cyclohexane to afford 5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (62.4 g, 78%). 1H NMR (400 MHz, CDCl3) δ: (ppm) 8.24 (s, 1H), 7.52-7.53 (m, 2H), 6.39 (t, 1H), 5.29-5.30 (m, 2H), 3.63-3.64 (m, 2H), 0.90 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1>C1COCC1.CCOCC>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:22]2([OH:25])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-bromo-2-methoxy-pyridine (Aldrich, 5.0 g, 26.6 mmol) in THF or ether (30 mL) at −78° C. was treated with n-BuLi (2.5 M in hexanes, 12 mL, 30 mmol) dropped slowly over 10 min. The reaction was stirred for an additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 4.37 g, 28 mmol) in THF (10 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for an additional 2 hours at −78° C. The reaction was then quenched with water and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system (Teledyne Isco, Inc, Lincoln, Nebr.) using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([CH3:19])[C@H:7]([NH:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([F:18])[N:12]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.CC1C=CC=C(C)N=1.CCOC(C)=O.CCCCCCC>C(Cl)Cl.O>[C:1]([O:5][C@H:6]([C@H:7]1[CH2:8][O:9][C:21](=[O:23])[N:10]1[C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([F:18])[N:12]=1)[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](OC(C)(C)C)[C@@H](CO)Nc1nc(F)ncc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: -70 °C
Reaction time: 90 h
Yield: 62.8 %

Procedure:
To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol) and a stir bar under nitrogen was added DCM (57 mL). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (0.93 g, 3.12 mmol) followed by the addition of 2,6-dimethylpyridine (2.64 ml, 22.7 mmol). The resulting reaction mixture allowed to warm to room temperature and stirred 90 hr at room temperature. The reaction mixture was then diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (0.59 g, 1.96 mmol, 35% yield) as a white crystalline. 1H NMR (400 MHz, CDCl3) δ 1.03 (s, 9H) 1.16 (d, J=6.65 Hz, 3H) 4.15 (qd, J=6.39, 1.96 Hz, 1H) 4.43-4.52 (m, 1H) 4.59-4.72 (m, 2H) 8.43 (d, J=1.57 Hz, 1H). LCMS m/z 246.0 (-t-butyl fragment) (M+H)+, Rt 0.88 min.
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2.Cl.[CH2:23](O)[CH3:24]>>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:20][CH2:23][CH3:24])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc2c(c1)SCC1CCCCC1C2=O
Agent: Cl
Product: CCOC(=O)C(C)c1ccc2c(c1)SCC1CCCCC1C2=O

Procedure:
To a solution of 2-(6,6a,7,8,9,10,10a,11-octahydro-11-oxodibenzo[b,e]thiepin-3-yl)propionic acid (10 g) in ethanol (150 ml) was added 35% hydrochloric acid (10 ml) and the mixture was heated under reflux for 4 hours. Removal of the ethanol under reduced pressure afforded the title compound (10.8 g), b.p. 205° C./0.06 mmHg. IR νmaxfilm cm-1 : 1720, 1660 (C=O). HRMS m/e: 332.1475 (M+) (Molecular weight calculated for C19H24O3S: 332.1447).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd].[C]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2c(O)cccn12
Temperature: 25 °C

Procedure:
31.45 g (101.3 mmol) of ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate were dissolved in 2 l of ethyl acetate, 3.15 g of 10% Pd/carbon were added and the mixture was stirred at RT and atmospheric pressure with hydrogen for 5 h. The mixture was filtered through kieselguhr, the filter cake was washed thoroughly with ethyl acetate/methanol and the filtrate was evaporated to dryness. This gave 21.94 g of the target compound (98% of theory, purity 99%).