Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:11])(=[O:10])[CH2:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:12]([NH2:15])(=[O:14])=[O:13].C(O)C>[Pd].CO>[S:1]1[C:5]2[S:6](=[O:10])(=[O:11])[CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[S:12]([NH2:15])(=[O:13])=[O:14]
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC=C2
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCC2
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
A solution of 6H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (3.05 g, 0.011 m) is absolute ethanol (130 ml) and methanol (20 ml) was hydrogenated on a Parr apparatus at 40 psi with 5% palladium on carbon catalyst (250 mg) at ambient temperature. After 15 minutes, 10% palladium on carbon catalyst (350 mg) was added, followed by an identical addition after 30 minutes. After 16 hours, the catalyst was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in absolute ethanol (100 ml) and methanol (50 ml) and hydrogenated at 50 psi with 10% palladium on carbon catalyst (500 mg) for 16 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The solid residue was chromatographed on silica gel, eluting with 10% methanol-chloroform to give 2.33 g (76%) of product.
Reaction SMILES: Br.[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][O:15]C(=O)C)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].O.[OH-].[Li+]>C1COCC1.O>[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)cc1
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CO)cc1
Reaction time: 1 h

Procedure:
To a solution of the acetate 4 (50.4 g) in 1.5 L of 3:1 THF/water at 0° C. was added lithium hydroxide monohydrate (18.9 g). After one hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.[Li]CCCC.[Na+].[Cl-]>C1COCC1>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([B:25]([OH:30])[OH:26])[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reaction time: 0.75 h
Yield: 120.5 %

Procedure:
To a solution of 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (4.00 g, 10.2 mmol) and triisopropyl borate (2.23 g, 11.8 mmol) in THF (60 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 6.50 mL, 10.4 mmol) keeping the internal temperature below −65° C. Stirring was continued at −78° C. for 45 min, again triisopropyl borate (1.11 g, 5.9 mmol) and n-BuLi (1.6 M in hexane, 3.25 mL, 5.2 mmol) were added and stirring was continued at −78° C. for 30 min. A 1 M aqueous solution of NaH2PO4.2H2O was added, saturated with solid NaCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuum to give the title compound as a yellow solid (4.39 g, 96%). MS (ISP) 358.2 [(M+H)+]; mp 140° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22](=[O:47])[C@H:23]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:24][C:25](=[O:39])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[NH2:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:47])[C@H:23]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH:24][C:25](=[O:39])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[NH:27][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-β-alanine was coupled with N-[3-[(benzyloxy)carbonyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester to give N-[3-[(benzyloxy)carbonyl]-N-[N-(t-butoxycarbonyl)-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 124°-125° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1>>[CH3:21][C:22]1[C:26]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[C:25]([CH3:30])[O:24][N:23]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(C)CC2=O

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3,5-dimethylisoxazole-4-boronic acid according to the coupling procedure described in example 21. MS m/z 256; HRMS: calcd for C16H17NO2+H+, 256.13321; found (ESI, [M+H]+), 256.1343.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.CN(C=O)C.[CH3:24][S-:25].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:25][CH3:24])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-β-carboline (Intermediate 5, 3.959 g, 14.9 mmol) and 100 ml anhydrous DMF. The resulting orange mixture was cooled to 0° C. (ice and water bath) and sodium thiomethoxide (1.809 g, 25.8 mmol) in powder form was added slowly thereto. The reaction mixture was stirred for 1 hr at 0° C., warmed to RT, and added slowly to a stirring mixture of 4:1 H2O/saturated aqueous sodium bicarbonate (500 ml). The precipitated solid was collected via suction filtration and air-dried to afford 4.017 g of 6-chloro-7-methylsulfanyl-8-nitro-9H-β-carboline as an orange powder. The crude material was used directly in subsequent steps.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([OH:17])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:20])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([Cl:20])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
Was prepared by stirring a mixture of 5-(4-nitrophenyl)-2-furoic acid (1.0 g, 4.3 mmol) and thionyl chloride (10 ml) at reflux for 2 hours. The mixture was evaporated and co-evaporated with anhydrous toluene. The acid chloride was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:28]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(O)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OS(C)(=O)=O)cc2)c1
Temperature: -20 °C
Yield: 95.5 %

Procedure:
Methyl 2-({3-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoate (0.096 g, 0.25 mmol) was dissolved in dichloromethane (10 ml) and cooled to −20° C. Triethylamine (0.039 g, 0.38 mmol) was added drop wise and methanesulfonyl chloride (0.032 g, 0.28 mmol) was added drop wise. The ice bath was removed and the mixture was wormed to room temperature. Diethyl ether (5 ml) was added and the precipitate filtered off. The organic phase was washed with two portions of brine (5 ml) and dried (MgSO4). Removing The solvent was removed by evaporation giving 0.109 gram of methyl 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}-ethyl)phenoxy]methyl}benzoate (yield 94.1%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[S]>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:15][CH:16]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1nccn1-c1ccc(C2=CCCn3c2cnc3C)cc1
Agent: [S]
Solvent: Clc1ccccc1Cl
Product: Cc1nccn1-c1ccc(-c2cccn3c(C)ncc23)cc1
Temperature: 25 °C

Procedure:
Combine 24 g (82.7 mmol) of the product of Example III with 10 g (0.31 mol) of sulfur in 500 ml of 1,2-dichlorobenzene and heat to reflux under nitrogen for 13 hr. Cool to room temperature and extract with 2× 500 ml of 10% hydrochloric acid. Combine the extracts and wash with 1 liter of methylene chloride and 500 ml of ethyl acetate. The aqueous phase is treated with charcoal, filtered, neutralized with sodium hydroxide, and extracted with 2×500 ml of methylene choride. Dry the combined extracts over magnesium sulfate and charcoal treat. Concentrate under vacuum to 200 ml rotal volume and isolate the title compound by column chromatography on 300 g of silica gel using 2% methanol/methylene chloride as solvent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12](C(OC(C)(C)C)=O)[CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14].FC(F)(F)C(O)=O>[Pd]>[CH3:11][NH:12][CH:13]([CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:3]=[C:4]2[O:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1)[CH3:14]
Reactant: Brc1cnc2ncoc2c1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1cnc2ncoc2c1

Procedure:
In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[C:10]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Br:25])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCOCC2)c2nc(Cl)ccc2n1
Reactant: OB(O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(N2CCOCC2)c2nc(-c3ccccc3Br)ccc2n1
Yield: 25.9 %

Procedure:
A solution of 2-amino-4-morpholino-6-chloro-pyrido[3,2-d]pyrimidine (265 mg, 1 mmol), potassium carbonate (690 mg, 5 mmol), tetrakis(triphenylphosphine)palladium(0) (100 mg) in dioxane (10 ml) and water (3 ml) was refluxed. To this refluxing solution was added dropwise (with a speed of 0.25 ml/min) a solution of 2-bromo-phenyl boronic acid (220 mg, 1.1 mmol) in dioxane (2 ml). Once the addition was complete, the reaction mixture was refluxed for another 2 hours. The reaction mixture was cooled down and the solvents were evaporated in vacuo. The residue was redissolved in dichloromethane and extracted with water. The combined organic layers were dried over Na2SO4 and the crude residue was purified by preparative TLC on silica, using a methanol/dichloromethane mixture in a ratio of 10:90 as mobile phase, yielding the pure title compound (100 mg, yield: 30%) which was characterised as follows: MS (m/z): 386, 388 ([M+H]+, 100).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][C@H:34]1[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1.O[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>C1COCC1>[O:39]=[C:37]1[NH:38][C@H:34]([CH2:33][O:32][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:35][CH2:36]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC[C@@H](COc2cccnc2)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of triphenylphosphine (52.46 g, 0.20 mol) in 400 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (31.49 mL, 0.20 mol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-5-(Hydroxymethyl)-2-pyrrolidinone (Aldrich Chemical Co., 15.19 g, 0.13 mol) and 3-hydroxypyridine (19.02 g, 0.20 mol) were added to the reaction vessel, and stirred for 16 hours. Solvent was removed in vacuo. The residue was diluted with CH2Cl2 and washed with 1N NaOH. After a brine wash (2×), the organic layer was dried over MgSO4. The residue was purified by silica gel flash chromatography using a gradient from 100% CHCl3 to 10% MeOH/CHCl3 (purification system was run twice), then recrystallized with ethyl acetate to give 4.0 g (16%) of the title compound as a white powder, mp.=121-122° C. TLC Rf =0.3 1 (10%MeOH/CHCl3). MS (DCI/NH3) m/e: 193 (M+H)+ and 210 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32-8.30 (m, 1H), 8.27 (dd, J=4.40, 1.50 Hz, 1H), 7.25-7.16 (m, 2H), 6.17 (br s, 1H), 4.14-4.08 (m, 1H), 4.05 (dd, J=8.80, 3.70 Hz, 1H), 3.89 (dd, J=8.80, 7.70 Hz, 1H), 2.49-2.23 (m, 3H), 1.99-1.87 (m, 1H). Anal. Calc. for C10H12N2O2 : C, 62.49; H, 6.29; N, 14.57; Found C, 62.53; H, 6.25; N, 14.71.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)[CH2:14][CH2:13]1.[NH3:23].O>C1(C)C=CC=CC=1>[NH2:23][C:15]([CH:12]1[CH2:14][CH2:13]1)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(N)C1CC1
Reaction time: 8 h

Procedure:
1.1 g of p-toluenesulphonic acid are added to 49.9 g (0.32 mol) of ethyl cyclopropylcarbonylacetate in 200 ml of dry toluene and the mixture is saturated with ammonia gas at room temperature with stirring. After allowing to stand overnight, the mixture is boiled under reflux for 8 hours in a water separator, ammonia gas being continuously introduced. The mixture is allowed to cool overnight and is filtered, and the toluene solution is concentrated in vacuo and removed by distillation in a high vacuum up to 65° C. from unreacted starting material. The substance is subsequently found in the residue.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[F-].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][CH:10]([CH3:12])[CH2:9][CH:8]([C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[N:7][CH:6]=1)[OH:13]
Reactant: CC(C)CC(O)c1cnc(Cl)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 14.9 %

Procedure:
To a solution of the 1-(2-chloropyrimidin-5-yl)-3-methylbutan-1-ol (600 mg, 2.99 mmol) in toluene (15.0 mL) was added Pd(PPh3)4 (346 mg, 0.299 mmol), 4-(trifluoromethyl)phenyl boronic acid (682 mg, 3.59 mmol), potassium fluoride (521 mg, 8.97 mmol) and water (3.7 mL). The reaction mixture was purged with nitrogen and heated to reflux for 5 h. The phases were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were concentrated under reduced pressure. The crude solid was purified by silica gel chromatography to give 3-methyl-1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butan-1-ol (138 mg) as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 8.55 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.81-4.84 (m, 1H), 1.92-1.65 (m, 2H), 1.53-1.47 (m, 1H), 0.94 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1.CN(CCN(C)C)C.CI>C1COCC1>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]([CH3:2])[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)Nc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
BuLi (2.2 M in cyclohexane, 22 mL, 48 mmol) was added dropwise at −78° C. to a solution of 6-chloro-1,3-dihydro-indol-2-one (4 g, 24 mmol) and TMEDA (11.2 mL, 79 mmol) in THF (100 mL) under N2. The solution was stirred for 30 minutes at the same temperature and then MeI (2.2 mL, 36 mmol) was added. The reaction mixture was warmed to −20° C. and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Chromatography gave the title compound (2.7 g) as a pale pink solid. MS: [M+H]+=182.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH3:16])=[O:4].[ClH:17].[F:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(O)C>[ClH:17].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]=3[O:15][CH3:16])=[O:4])[CH2:27][CH2:26]2)=[O:24])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1c(C(=O)CBr)ccc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(C(=O)CN2CCC(C(=O)c3ccc(F)cc3)CC2)ccc2ccccc12

Procedure:
1.5 g of 2-bromo-1'-methoxy-2'-acetonaphthone, 1.3 g of 4-(p-fluorobenzoyl)piperidine hydrochloride, and 1.6 g of triethylamine were added to 60 ml of ethanol. The mixture was refluxed for 15 min. The solvent was distilled off, and dichloromethane was added to the residue. The mixture was washed with water and dried. The dichloromethane was distilled off, and the residue was purified by column chromatography (silica gel) to prepare an oleaginous intended compound. The compound was converted into a hydrochloride by an ordinary method and then recrystallized to prepare 1.38 g of an intended hydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:18])([F:19])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC(F)(F)F
Yield: 79 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.81 ml (0.013 mol) of triethylamine, 1.1 ml (0.013 mol) of 2,2,2-trifluoroethylamine in 30 ml of DMF were reacted at 40° C. for 48 hours affording 4.71 g of oil. This oil was kugelrohr distilled at 53 Pa, pot temperature 110°-120° C. to give 2.82 g (47.3%) of product as a yellow oil, nD25 1 4496.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]2[O:4][C@@H:2]12.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>N1C=CC=CC=1>[Si:19]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[C@@H:2]2[O:4][C@H:3]12)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2O[C@H]21
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2O[C@@H]21
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To a stirred solution of 9.5 g (38.1 mmol) of 2',3'-anhydroadenosine (Robins, M. J.; Hansske, F; Low, N. H.; Park, J. I. Tetrahedron Lett. 1984, 367-370) in 114 mL of pyridine was added 11.5 g (76.2 mmol) of t-butyldimethylsilyl chloride. After 3.5 h at room temperature, an additional 5.75 g (38.1 mmol) of t-butyldimethylsilyl chloride was added. After a total of 4.25 h, the reaction mixture was diluted into 2 L of water and extracted with 3×500 mL of dichloromethane. The combined dichloromethane extracts were washed with one liter of saturated aqueous sodium bicarbonate, with 3×500 mL of water, and then dried over magnesium sulfate. Concentration under reduced pressure afforded 13.3 g of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine. To a stirred solution of 2.0 g (5.50 mmol) of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine in 55 mL of THF at 0° C. was added 22 mL (22 mmol) of a 1M solution of lithium triethyl borohydride in THF. The reaction mixture was then allowed to warm to room temperature. After 3 hours, the reaction mixture was recooled to 0° C. and then carefully treated with 4.0 mL of 5% aqueous acetic acid. The resulting mixture was diluted with 150 mL of EtOAc, washed with 3×100 mL of saturated aqueous NaCl, dried over magnesium sulfate, concentrated under reduced pressure, and then coevaporated with three portions of chloroform. Chromatography of the residue on silica gel with a 100:0 to 97:3 chloroform/methanol gradient afforded 1.8 g (90%) of the title compound: colorless glass; Rf =0.10 (silica gel 60 F-254, 0.25 mm, E. Merck (SG), 95:5 CHCl3 :MeOH); [α]D23 -47.8° (c 2.47, CHCl3); IR (CDCl3) 3480, 3415, 3320, 3165, 3125, 2960, 2935, 2860, 1635, 1595, 1575, 1470, 1415, 1330, 1290, 1255, 1210, 1135, 1090, 995 cm-1 ; 1H NMR (300 MHz, CDCl3, TMS=0.00 ppm) δ0.08, 0.09 (2s, 6H, (CH3)2Si), 0.88 (s, 9H, (CH3)3CSi), 2.10 (ddd, 1H, J=13.5 Hz, J'= 6.5 Hz, J"=4.0 Hz, 3'-H), 2.34 (ddd, 1H, J=13.5 Hz, J'=7.5 Hz, J"=6.0 Hz, 3'-H), 3.74 (dd, 1H, J=12.0 Hz, J'=3.0 Hz, 5'-H), 4.05 (dd, 1H, J=12.0 Hz, J'=3.0 Hz), 4.62 (dddd, 1H, J=7.5 Hz, J'=6.5 Hz, J"=J'"=3.0 Hz, 4'-H), 4.70 (ddd, 1H, J=6.0 Hz, J'=4.0 Hz, J"=2.5 Hz, 2'-H), 5.88 (bs, 1H, OH), 6.01 (d, 1H, J=2.5 Hz, 1'-H), 6.15 (bs, 2H, NH2), 8.30, 8.33 (2s, 2H, H-2, H-8); FAB MS, m/z 366 (M+H)+ , 136.