Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]Cl)=[CH:39][CH:38]=1>CN(C=O)C>[C:1]1([C:7](=[N:8][C:9]([CH3:10])([CH2:43][C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[C:11]([O:13][CH3:14])=[O:12])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reactant: ClCc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of methyl N-(diphenylmethylene)alaninate from Step A (9.78 g, 36.6 mmol) in 60 ml DMF at 0° C. was added a 1M solution of sodium bis(trimethylsilyl)amide in THF (45.72 ml, 45.72 mmol) over a 20 min period. After 30 min, a solution of 4-picolyl chloride hydrochloride (3.00 g, 18.29 mmol) in 40 ml DMF was added to the reaction via canula over a 25 min period. The reaction was warmed to rt and stirred for 5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 3M LiCl (2×) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-40% EtOAc/hexanes) afforded methyl 2-[(diphenylmethylene)amino]-2-methyl-3-pyridin-4-ylpropanoate as a white solid (5.28 g, 81%). LCMS [M+H]=359.2. 1H NMR (d4-MeOH) δ 8.51 (dd, J=4.5, 1.5 Hz, 2H), 7.56 (dd, J=8.4, 1.4 Hz, 2H), 7.40-7.37 (m, 4H), 7.34-7.30 (m, 2H), 7.26-7.23 (m, 2H), 7.10-7.07 (m, 2H), 3.33 (A of AB, d, J=13.0 Hz, 1H), 3.27 (s, 3H), 3.18 (B of AB, d, J=12.9 Hz, 1H), 1.32 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:26][CH3:27])=[C:21](B(O)O)[CH:22]=1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:18]=[C:17]([F:16])[CH:22]=[CH:21][C:20]=2[S:26][CH3:27])[C:11]=1[CH3:12]
Reactant: CSc1ccc(F)cc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: CSc1ccc(F)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (270 mg, 1.10 mmol) and 5-fluoro-2-(methylthio)phenylboronic acid to give 4-chloro-5,7-difluoro-2-(5-fluoro-2-(methylthio)phenyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=354.1 (M+1).
Reaction SMILES: C([C:3]1[C:4]([B:22]2[O:26][C:25]([CH3:28])(C)C(C)(C)[O:23]2)=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.C[N+:32]([O-:34])=[O:33].[OH-].[Na+].Cl>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Br-].C1COCC1.O>[C:14]([O:13][C:12](=[O:18])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[C:4]2[B:22]([OH:23])[O:26][CH:25]([CH2:28][N+:32]([O-:34])=[O:33])[C:3]=2[CH:21]=[CH:20][CH:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCCOc1cccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53.9 %

Procedure:
To a solution of tert-butyl 4-(3-formyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy)-butylcarbamate (3.5 g, 8.3 mmol) and CTAB (cat.) in THF (50 mL) was added MeNO2(2.8 mL, 49 mmol), followed by an aqueous solution of NaOH (0.36 g, 9.1 mmol) in H2O (5 mL). The mixture was stirred at room temperature for 45 min. The cyclization was afforded by adding 2N HCl solution until pH=2 at 0° C. The reaction mixture was extracted with EtOAc (3×50 mL) and the organic layers were dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (PE: EtOAc=3:1) to give the product as yellow oil (1.7 g, yield 53.6%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.44-7.47 (t, 1H), 7.06-7.08 (d, 1H), 6.88-6.90 (d, 1H), 9.86 (t, 1H), 5.70-5.72 (m, 1H), 5.29-5.33 (m, 1H), 4.53-4.59 (m, 1H), 4.02-4.06 (t, 2H), 2.95-2.30 (m, 2H), 1.67-1.72 (m, 2H), 1.52-1.57 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH3:11].[Li]C(C)(C)C.CO[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1>C(OCC)C>[Cl:9][C:4]1[C:3]([O:10][CH3:11])=[C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: COc1c(Cl)cc(Cl)cc1Br
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1c(Cl)cc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-Bromo-3,5-dichloro-2-methoxybenzene (Preparation 25, 4.4 g, 17.5 mmol) in 95 ml diethylether was cooled to −78° C. under nitrogen. tBuLi (10 ml, 35.16 mmol) was added dropwise and the reaction stirred for 15 minutes. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.58 g, 29 mmol) was added and the reaction stirred at −78° C. for 1 hour before pouring the reaction into 50 ml ice cold ammonium chloride (aqueous). The product was extracted with diethylether (3×30 ml), the combined organic layers were washed with water (50 ml) and brine (2×25 ml), dried over sodium sulphate, and concentrated in vacuo to afford a yellow oil. This was purified using silica gel column chromatography (heptane:ethyl acetate 9:1) to furnish a yellow oil, 4.5 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 24 h

Procedure:
To a stirred mixture of 2.5 g of 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and 2.8 g of powdered potassium carbonate in 25 mL of dry N,N-dimethylformamide was added methyl iodide (0.94 mL) at 5° C. Stirring was continued for 24 hours at room temperature. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and the solvent was removed in vacuo. The crude product (2.7 g; oil) was used in the next step without further purification. EI-MS: 263 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.[OH-].[Na+].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S(=O)(=O)(O)O>O.CO>[OH:28][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Temperature: 20 °C
Yield: 84.4 %

Procedure:
Example 1 from EP 0,257,151 is duplicated. 2-nitro-2'-hydroxy-3', 5'-di-t-amylazobenzene (12.8 g) is added to a mixture of methanol (41 g), water (10 g) and 97% sodium hydroxide (11 g), and the resultant mixture is stirred at 65° C. for 30 minutes. Thereafter, 9-fluorenone (2.0 g) and then glucose (12 g) are added to the mixture at 60° to 65° C. over 4 hours. The resultant mixture is further stirred for 4 hours at the boiling point (70° C.), thus completing the reduction reaction. Thereafter, water (50 ml) is added to the reaction liquor, and the reaction liquor is neutralized with 62% sulfuric acid (13 g). The liquor thus neutralized is cooled to 20° C. to precipitate a crystal. The crystal thus obtained is separated by filtration, and the separated crystal is fully washed with water and further with methanol. The washed crystal is then dried, thus producing 9.9 g of 2-(2'-hydroxy-3', 5'-di-t-amylphenyl)benzotriazole having a melting point of 77° to 79° C. at the yield of 85.0%. One can see that the reduction reaction with the aromatic ketone 9-fluorenone takes over 81/2 hours to complete and requires three times as much catalyst.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.S(Cl)([Cl:14])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([Cl:14])[CH2:6][CH2:5]2
Reactant: O=S(Cl)Cl
Reactant: OC1CCc2cc(Br)ccc21
Solvent: ClCCl
Product: ClC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.1 (2.0 g) in DCM (10 mL) in an ice-bath, was treated with thionyl chloride (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The resulting material was chromatographed on a silica gel column, eluting with 5-10% EtOAc in hexane, to afford 1.2. 1H NMR (DMSO-d6) δ 7.54 (s, 1H), 7.45 (dd, 1H, J1=1.0 Hz, J2=8.50 Hz), 7.37 (d, 1H, J=8.0 Hz), 3.07 (m, 1H), 5.60 (q, 1H), 2.93 (m, 1H), 2.59 (m, 1H), 2.26 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](Cl)[CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])[CH:10]=1)=[O:4].[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])[C:8]([CH:21]2[CH2:23][CH2:22]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Cl)cc(-c2cc(OC)ccc2F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2CC2)c(-c2cc(OC)ccc2F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a round bottom flask containing 13.2 (0.46 g, 1.56 mmol), cyclopropylboronic acid (0.40 g, 4.67 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.26 g, 0.638 mmol), palladium acetate (0.07 g, 0.31 mmol), and potassium phosphate tribasic (1.00 g, 4.71 mmol), was added a premixed solution of 1,4-dioxane (1.0 mL) and water (0.3 mL). The mixture was stirred at room temperature for 5 minutes and then heated to 88° C. and monitored with TLC. After 4 hours, the reaction was cooled to room temperature and diluted with EtOAc. The mixture was then filtered through a pad of silica gel (eluting with EtOAc) and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 25% EtOAc in hexanes) to yield a colorless oil 13.3 (0.4 g, 85% yield.) 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (2H, m), 7.07 (1H, t, J=8.8 Hz), 6.96 (1H, d, J=8.2 Hz), 6.91 (2H, m), 3.89 (3H, s), 3.81 (3H, s), 1.84 (1H, dt, J=8.6, 4.3 Hz), 0.93 (2H, m), 0.75 (2H, m).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([OH:8])[NH:5][N:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:5]1[C:6]([OH:8])=[CH:7][C:3]([C:2]([F:10])([F:9])[F:1])=[N:4]1
Reactant: Oc1cc(C(F)(F)F)n[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cc(C(F)(F)F)nn1C1CCCCO1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
3-(Trifluoromethyl)-1H-pyrazol-5-ol (5.0 g, 0.032 mole) which is known in the art and p-toluene-sulfonic acid monohydrate (0.08 g) were dissolved in ethyl acetate (30 mL) and warmed to 50° C. 3,4-Dihydro-2H-pyran (2.9 g, 0.034 mole) was slowly added over a 10 minute period. After stirring 30 minutes at 50° C., the mixture was cooled and diluted with 100 mL of ethyl acetate. This solution was washed twice with 0.5% hydrochloric acid solution, then dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was treated with 5 mL of ethyl acetate and 20 mL hexanes and filtered to give 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (5.8 g, 76% yield) as a white solid, mp=129°-130° C.
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:1](=[O:18])[O:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.65 g, 6.6 mmol) was added to a solution of N-methyl-1-(3-nitrophenyl)methanamine (1 g, 6 mmol) in CH2Cl2 (24 mL) and DIEA (2.7 mL, 15 mmol) and the reaction mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 (100 mL), washed with NH4Cl, NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo to yield 60A (1.75 g, 99%) as a white solid. MS (ESI) m/z 301.03 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:19]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:16][CH2:15][CH2:14][N:13]([CH3:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:18]=1.Cl.[H][H]>CO.[Pd]>[Cl:1][C:2]1[C:3]([NH2:19])=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:16][CH2:15][CH2:14][N:13]([CH3:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CN1CCCN(c2nc3cc(Cl)c([N+](=O)[O-])cc3o2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 50 mg portion of 5-chloro-6-nitro-2-(4-methyl-1-homopiperazinyl)benzoxazole was dissolved in 15 ml of methanol, and the resulting solution was mixed with 5 ml of 1 N hydrochloric acid aqueous solution and 30 mg of Pd/C catalyst and, after replacing the atmosphere in the reaction container by hydrogen gas, stirred at room temperature for 15 hours. The catalyst was removed by filtration and the solvent was concentrated under a reduced pressure. The thus remained oily matter was mixed with 5 ml of 1 N hydrochloric acid and washed with ethyl acetate. This was adjusted to pH 8 by adding saturated sodium bicarbonate, and the thus precipitated crystals were collected by filtration to obtain the title compound (16 mg).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[Cl:39][C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][C:43]([C:49]([F:52])([F:51])[F:50])=[N:42][CH:41]=1>>[Cl:39][C:40]1[C:45]([C:46]([N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]4[CH:18]=[C:17]([C:19]5[C:20]6[CH:27]=[CH:26][NH:25][C:21]=6[N:22]=[CH:23][N:24]=5)[CH:16]=[N:15]4)[CH2:11]3)[CH2:6][CH2:5]2)=[O:47])=[CH:44][C:43]([C:49]([F:51])([F:50])[F:52])=[N:42][CH:41]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ncc1Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: Cl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(C(F)(F)F)ncc3Cl)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 5-chloro-2-trifluoromethylisonicotinoic acid following the procedure described for Example 1, followed by HPLC purification (method B) provided the title compound. LC-MS: 570.2 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 12.08 (brs, 1H), 8.92 (, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.11 (d, J=14.09 Hz, 1H), 7.59 (d, J=3.30 Hz, 1H), 7.04 (d, J=3.30 Hz, 1H), 4.07 (m, 1H), 3.73 (m, 2H), 3.56 (m, 2H), 3.52 (s, 2H), 3.26 (m, 2H), 2.98 (m, 1H), 2.53 (m, 1H), 1.69 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:22][CH:21]=[N:20][CH:19]=2)=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O>[O:22]1[C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH2:7])=[CH:9][CH:10]=2)=[CH:19][N:20]=[CH:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnco2)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnco2)c2ccccc12
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Compound 503C (1.34 g, 4.3 mmol) was dissolved in trifluoroacetic acid (10 mL) and the resulting mixture was allowed to stand for 1 h at room temperature. After removing the volatiles in vacuo, the residue was co-evaporated from ethyl acetate/heptane (2×50 mL) to remove traces of trifluoroacetic acid. After partitioning the residue between ethyl acetate (100 mL) and 1N NaOH (75 mL), the organic layer was washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 900 mg (99%) of compound 503D as a yellow crystalline solid. HPLC conditions: 95% at 0.92 min (retention time) (Phenomenex 5 micron ODS column, 4.6×30 mm, 10%-90% aqueous methanol over 2 min gradient with 0.1% TFA, monitoring at 254 nm.). MS (ES): m/z 211.22 [M+H]+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.CCOC(C)=O.O>[CH2:32]([C:29]1[N:28]=[C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[F:34])[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])[O:31][N:30]=1)[CH3:33]
Reactant: OB(O)c1ccccc1F
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 4-{6-bromo-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (250 mg, compound B99), (2-fluorophenyl)boronic acid (65 mg), dichlorobis(tricyclohexylphosphine)palladium (17 mg) and aqueous cesium carbonate solution (0.35 ml, 2.0 M) are placed in a microwave tube and DME (8 ml) is added. The reaction vessel is sealed and the mixture is subjected to microwave irradiation at 150° C. with stirring for 20 min. The mixture is allowed to cool to RT and additional (2-fluorophenyl)boronic acid (19 mg) and dichlorobis(tricyclohexylphosphine)palladium (9 mg) are added. The mixture is again subjected to microwave irradiation at 150° C. with stirring for 20 min and then allowed to cool to RT. After addition of water and extraction with EtOAc the combined organic layers are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. All volatile materials are removed in vacuo and the residue is purified by flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/1 (v/v)] to afford tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate as a solid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([CH3:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36])([O-:26])=[O:25]>C(Cl)Cl.O>[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([CH3:39])[CH2:34][S:35]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])(=[O:37])=[O:36])([O-:26])=[O:25]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(CS(=O)(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)CC(C)c3ccccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: -15 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
242 mg thymidine (1 mmol, co-evaporated 3× each with 5 ml abs. pyridine) are dissolved in 2.5 ml abs. pyridine and cooled to -60° C. 396 mg 2-(2-nitrophenyl)propylsulfonyl chloride (1.5 mmol) in 2.5 ml abs. CH2Cl2 are added drop-wise to this within 10 Min. After stirring 4 h at a temperature between -60 and -30° C., the temperature is allowed to increase to -15° C. After a total of 61/4 h, the reaction is mixed with 15 ml H2O and CH2Cl2 respectively and the aqueous phase is extracted 4× each with 15 ml CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and rotary evaporated. This is co-evaporated 3× with toluene and 1× with methanol. The crude product (600 mg) is purified over flash chromatography (39 g silica gel, 3×11 cm, Sol.: CH2Cl2 /MeOH, cond.: CH2Cl2, gradient: 100 ml CH2Cl2, each 150 ml 100:1, 100:2, 100:3 and 100:4). 290 mg (0.62 mmol, 62%) 5'-O-[2-(2-nitrophenyl)propyl-sulfonyl]-thymidine are obtained as a colorless foam. The obtained mixed fractions are purified by a further column (4.5 g silica gel, 1×11 cm, Sol.: CH2Cl2 /MeOH, cond.: CH2Cl2, gradient: 100 ml CH2Cl2, each 50 ml 100:0.5, 100:1 and 100:2). 128 mg (0.18 mmol, 18%) 3',5'-Di-O-[2-(2-nitrophenyl)-propylsulfonyl]-thymidine are isolated as a colorless foam and 26 mg (0.06 mmol, 6%) 3 '-O-[2 -(2-nitrophenyl)-propylsulfonyl]-thymidine as a light red foam.
Reaction SMILES: [K+].[Br-].[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:30][C:28](=[O:29])[CH2:27][C@H:26]([OH:31])[C@@H:25]([CH3:32])[C:23](=[O:24])[C@H:22]([CH3:33])[C@@H:21]([OH:34])[C@@H:20]([CH3:35])[CH2:19][CH2:18][CH2:17][C@H:15]3O[C@H:14]3[CH2:13]2)\[CH3:11])[N:5]=1.CC1SC=C(/C=C/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)N=1>CO>[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:30][C:28](=[O:29])[CH2:27][C@H:26]([OH:31])[C@@H:25]([CH3:32])[C:23](=[O:24])[C@H:22]([CH3:33])[C@@H:21]([OH:34])[C@@H:20]([CH3:35])[CH2:19][CH2:18][CH2:17][CH:15]=[CH:14][CH2:13]2)\[CH3:11])[N:5]=1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1
Agent: Cc1nc(/C=C/[C@@H]2C[C@@H]3O[C@@H]3CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O2)cs1
Agent: [Br-]
Solvent: CO
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1

Procedure:
colorless amorphous solid; [α]D22−114.0 (c 10.0, MeOH); UV (MeOH) λmax nm (ε) 211 (16500), 248 (12500); IR (KBr) νmax 3440, 2933, 2877, 2858, 1730, 1708, 1457, 1244,981 cm1; 1H NMR (CDCl3, 300 MHz) δ 6.96 (1H, s, H-19), 6.56 (1H, bs, H-17), 5.47 (1H, dd, J=9.2, 3.0 Hz, H-15), 5.43 (1H, m, H-12), 5.40 (1H, m, H-13), 4.40 (1H, ddd, J=6.2, 6.1, 6.1 Hz, H-3), 3.69 (1H, dd, J=5.7, 3.6 Hz, H-7), 3.01 (1H, dq, J=5.7, 6.9 Hz, H-6), 3.01 (1H, bs, 3-OH), 2.84 (1H, dq, J=5.2, 7.0 Hz, H-4), 2.68 (3H, s, H-21), 2.66 (1H, ddd, J=16.4, 9.2, 7.3 Hz, H-14a), 2.64 (1H, dd, J=15.9, 7.1 Hz, H-2a), 2.54 (1H, dd, J=15.9, 6.1 Hz, H-2b), 2.38 (1H, bd, J=16.4 Hz, H-14b), 2.35 (1H, bs, 7-OH), 2.07 (3H, bs, H-27), 2.03 (2H, m, H-11), 1.62 (1H, m, H-10a), 1.53 (1H, m, H-8), 1.35 (1H, m, H-9a), 1.22 (1H, m, H-9b), 1.19 (3H, d, J=6.9 H, H-24), 1.14 (3H, d, J=6.9 Hz, H-23), 1.10 (1H, m, H-10b), 0.95 (3H, d, J=6.9 Hz, H-25), 13C NMR, see Table 1; EIMS m/z 463 [M]+ (5), 324 (8), 290 (8), 204 (7), 168 (100), 164 (15), 139 (36); HREIMS m/z 463.2381 (calcd. for C25H37NO5S, 463.2392).