Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[C:14]([O:19][CH3:20])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[F:21][C@@H:22]1[CH2:26][NH:25][CH2:24][C@H:23]1[NH:27][C:28](=[O:35])[CH2:29][CH2:30]S(C)(=O)=O.C(N(CC)C(C)C)(C)C.CC(C)([O-])C.[K+].P([O-])([O-])([O-])=O>CS(C)=O.C1COCC1.O>[F:21][C@@H:22]1[CH2:26][N:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]3[C:14]([O:19][CH3:20])=[N:15][N:16]([CH3:18])[CH:17]=3)[N:3]=2)[CH2:24][C@H:23]1[NH:27][C:28](=[O:35])[CH:29]=[CH2:30]
Reactant: COc1nn(C)cc1Nc1nc(F)nc2c1ncn2C
Reactant: CS(=O)(=O)CCC(=O)N[C@@H]1CNC[C@H]1F
Agent: CC(C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@@H]1CN(c2nc(Nc3cn(C)nc3OC)c3ncn(C)c3n2)C[C@H]1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (554 mg, 2.00 mmol, 1.00 eq) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (500 mg, 2.10 mmol, 1.05 eq) in DMSO (4.2 mL) was added N,N-diisopropylethylamine (0.83 mL, 5.00 mmol, 2.50 eq). The reaction mixture was then heated at 100° C. for 16 hr, cooled to ambient temperature, diluted with THF (4 mL), and treated with potassium tert-butoxide (4.00 mL, 1 M in THF, 2.00 eq). After 1 hr, an additional portion of potassium tert-butoxide (0.50 mL, 1 M in THF, 0.25 eq) was added to the reaction mixture. After a further 1 hr, the reaction mixture was poured into phosphate buffer (50 mL, pH=7) and water (50 mL), and extracted with ethyl acetate (5×40 mL). The combined organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. This crude product was then dissolved in ethyl acetate (40 mL) at 60° C. and then treated with heptanes (20 mL), at which point the solution became cloudy and was allowed to cool to ambient temperature and then to 0° C. After 16 hr at 0° C., the resulting solids were filtered and dried at ambient temperature to give the title compound (620.5 mg, 75% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C18H23FN9O2 416.3 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[N:9]=[CH:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH2:35]([S:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[N:9]=[CH:10][C:3]=12)[CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ncc3c(S)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2ncc3c(SCC=Cc4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.17 h

Procedure:
A suspension of 4-mercapto-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (1.0 g) and potassium carbonate (0.37 g) in N,N-dimethylformamide was stirred for 10 minutes and then cinnamyl bromide (0.53 g) was added. After stirring for 3 hr. at 40° C. the solution was filtered and 100 ml chloroform was added. The solution was extracted with water. The chloroform layer was dried, filtered and taken to dryness on a rotary evaporator. The residue was purified on a column of silica gel using chloroform as the eluant. The fractions containing the product were pooled and taken to dryness in vacuo. The residue was dissolved in chloroform, filtered through a Millipore filter in vacuo and evaporated in vacuo, to give the product 4-cinnamylthio-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][C:7]3([O:17][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][NH:9][CH2:8]3.C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].CCCCCC.CCOCC>ClCCl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][C:7]3([O:17][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:8]3
Reactant: CCC(=O)Cl
Reactant: Clc1ccc2c(c1)OC1(CNCc3ccccc31)C2
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=O)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a cooled solution of 6-chlorospiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (6.0 g) and triethylamine (2.4 g) in dichloromethane (50 ml) is slowly added dropwise propionyl chloride (2.3 g) in dichloromethane (20 ml). The reaction mixture is stirred for 18 hours at ambient temperature, washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield an oil which, upon trituration with hexane/ether, yields product as a white solid (6.6 g, 92%). An analytical sample is recrystallized from hexane to yield a white solid, mp 106°-107°.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[S:8][C:7]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:5]
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnc(CNC(=O)c2cc3ccccc3[nH]2)n1-c1sc(C(=O)O)cc1C(=O)c1ccccc1Cl
Yield: 34.9 %

Procedure:
Ethyl (3-(2-chlorobenzoyl)-2-(3-(2-indolecarbonylaminomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)carboxylate (0.16 g) was hydrolyzed using a 2M aqueous sodium hydroxide solution (0.22 ml) and methanol (1 ml) to give 0.053 g of (3-(2-chlorobenzoyl)-2-(3-(2-indolecarbonylaminomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)carboxylic acid.
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3](OC)=[O:4].C[O-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].Cl>CCOCC>[Cl:7][CH:2]([Cl:1])[C:3](=[O:4])[CH2:21][C:20]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([F:11])[CH:13]=1)=[O:22]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: COC(=O)C(Cl)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(C(=O)CC(=O)C(Cl)Cl)cc1F

Procedure:
Methyl dichloroacetate (1.57 g, 11 mmol) was dissolved ether (25 mL). To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol) followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (1.68 g, 10 mmol). After stirring 16 hours 1N HCl (25 mL) was added. The organic layer was collected and washed with water (2×25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude dione was used in the next step without further purification or characterization.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[CH2:19][N:18]([CH3:24])[CH2:17][CH:16]2[C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[CH2:19][N:18]([CH3:24])[CH2:17][CH:16]2[C:25]1[CH:26]=[C:27]([S:31]([NH:1][CH2:2][CH2:3][P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1
Reactant: CCOP(=O)(CCN)OCC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: ClCCl
Product: CCOP(=O)(CCNS(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of diethyl 2-aminoethylphosphonate (100 mg, 0.55 mmol, 1.00 equiv) in dichloromethane (10 mL) with TEA (220 mg, 2.18 mmol, 3.94 equiv). This was followed by the addition of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.60 mmol, 1.08 equiv, 78%) in several batches. The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (50:1). This resulted in 0.07 g (24%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([OH:25])=O)[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=1[CH2:30][C:31]1[CH:32]=[C:33]2[NH:39][CH2:38][C:37]([CH3:41])([CH3:40])[C:34]2=[N:35][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([CH2:30][C:29]4[CH:42]=[CH:43][CH:44]=[CH:45][C:28]=4[F:27])[CH:32]=3)[C:37]([CH3:41])([CH3:40])[CH2:38]2)=[O:25])[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccccc3F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 4.04 mmol) and 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.14 g, 4.45 mmol) in DMF (20.2 mL) were added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.31 g, 6.1 mmol) and N,N-diisopropylethylamine (1.41 mL, 8.1 mmol) at room temperature. The reaction was stirred at room temperature for 18 h. Saturated aqueous sodium hydrogen carbonate was added and the mixture extracted with diethyl ether (3×). The combined organic extracts were washed with water (3×) and brine (3×) then dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (1.43 g), MS: [M+H]+=610.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1SC.[CH3:15][NH:16][CH3:17]>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[N:16]([CH3:17])[CH3:15]
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Reactant: CNC
Product: CCC(C)c1nnc(N(C)C)n(N)c1=O
Yield: 93 %

Procedure:
Analogously to the procedure described in Example 5, reaction of 42.8 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5 (4H)-one with dimethylamine gave 39.4 g (93% of theory) of 4-amino-6-sec.-butyl-3-dimethylamino-1,2,4-triazin-5 (4H)-one in the form of a viscous oil.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]([C:13]1[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH:14]=1)=[O:12]>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:8])[N:15]([CH:18]([CH3:20])[CH3:19])[CH:14]=1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccn(C(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)n(C(C)C)c1
Reaction time: 4 h

Procedure:
NBS (36.6 mmol) was added to a mixture of 1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step D5) (37.4 mmol) in CCl4 (250 mL). After 4 h, the reaction mixture was successively washed with a saturated aqueous solution of NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a pale yellow-pink oil. tR: 4.56 min (HPLC 1); ESI-MS: tR=1.13 min, [M+H]+ 246/248 (LC-MS 1); TLC: Rf=0.35 (1:6 EtOAc/heptanes).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[C:19]=1[NH2:27].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[C:19]=1[NH:27][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]c2nccc(Nc3c(Cl)ccc4c3OCO4)c2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Compound 83 (250 mg, 1.08 mmol), 5-chloro-benzo[1,3]dioxol-4-ylamine (279 mg, 1.63 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), X-Phos (52 mg, 0.11 mmol), and NaOtBu (312 mg, 3.25 mmol) were suspended in dioxane (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 188 (301 mg, 76% yield) as a white solid. LC-MS (M+H=366, obsd.=366).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[H-].[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17]>O1CCCC1>[O:18]=[C:16]([CH3:17])[CH2:15][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: CC(=O)CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 40 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
Phthalimide (3 g) was dissolved in dry tetrahydrofuran (70 ml) and added dropwise at room temperature to a suspension of sodium hydride (539 mg) in tetrahydrofuran (15 ml). This was followed by heating at 40° C. for one hour, and then a solution of chloroacetone (1.99 g) dissolved in tetrahydrofuran (15 ml) was added dropwise. The mixture was then kept at the reflux temperature for 15 hours. After cooling, it was added to an ice/water mixture and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (n-heptane/ethyl acetate 2:1). 2.9 g of the title compound were isolated.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.Cl>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[C@@H:15]([CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=1)[CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -68 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a 3-necked 5 L RBF is added THF (2 L) and (4S)-4-benzyl-3-butanoyl-oxazolidin-2-one (270 g 1.09 moles) under N2. The resulting solution is cooled to −68° C. in an acetone-dry ice bath. To the cold solution is added sodium bis(trimethylsilyl)amide (1320 mL of 1M THF solution; 1.32 moles) dropwise over 1.5 h while the internal temperature is held between −68 to −60° C. Upon completion of the addition, the reaction is stirred at −68° C. for 30 min. To the cold solution is then added 4-trifluoromethylbenzyl bromide (278 g; 1.16 moles) in THF (1 L) over 30 min at −68° C. After 1.5 h, the reaction is poured into 1 M HCl. The mixture is extracted with ethyl acetate (3 L×1). The extracts are combined and washed with aq. NaHCO3 (2 L×1) and brine (2 L×1). The organic phase is dried over Na2SO4, filtered, and concentrated. The solid is triturated with EtOH (600 mL) at 15° C. Filtration provides the title compound as a solid (270 g, MS:[M+H]+=406 m/z).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]([CH2:14][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)#[N:16]
Reactant: N#CCCl
Reactant: Oc1ccc(-c2cccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A mixture of 4-(2-thienyl)phenol (1.30 g), chloroacetonitrile (668 mg) and potassium carbonate (1.53 g) in DMF (7 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with H2O and the separated solid was recovered to give 1.45 g of 2-(4-cyanomethoxyphenyl)thiophene.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1>CCO.[Pt]=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:12])[F:13])[N:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(C(F)(F)F)ncc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)ncc1N

Procedure:
A suspension of platinum oxide (36.9 mg) in a solution of 4-methyl-5-nitro-2-(trifluoromethyl)pyridine (369.4 mg, 0.162 mmol) in EtOH (12.7 mL) was stirred under a balloon of H2 for 5½ h. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford 4-methyl-6-(trifluoromethyl)pyridin-3-amine. LCMS calc.=177.1; found=177.1 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 8.04 (s, 1H); 7.27 (s, 1H); 4.28 (s, 2H); 2.15 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:18][S:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:29])=[O:28])[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NC1Cc2ccc(O)cc2C1)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=C(NC1Cc2ccc(OS(=O)(=O)c3ccccc3)cc2C1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
95 mg (0.35 mmol) 4-fluoro-N-(5-hydroxy-indan-2-yl)-benzamide were dissolved in 2 ml of pyridine, 120 mg (0.72 mmol) of benzenesulfonic acid chloride were added, and the mixture was stirred for 5 h at 70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[CH2:46][NH2:47]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:47][CH2:46][CH:42]4[CH2:43][CH2:44][CH2:45][O:41]4)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCC1CCCO1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Product: CN(CCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21)C(=O)OCc1ccccc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (tetrahydro-2-furanylmethyl)amine using conditions similar to Example 497: ES+ MS: 603 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].[CH2:28]1COCC1>>[CH2:1]([CH:3]([O:6][C:7]1[C:16]2[N:15]([CH3:28])[C:14](=[O:17])[CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc2c1NC(=O)CN2c1c(C)cc(C)cc1C
Reactant: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c1N(C)C(=O)CN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 8-(1-ethyl-propoxy)-6-methyl-4-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg, 0.136 mmol) in 3 ml of dry THF was added 1.0M of LiN[Si(CH3)3]2 in THF (0.14 ml, 0.14 mmol) at −78° C. After stirring at that temperature for 20 min, the reaction mixture was warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and saturated ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated to give 51 mg of a golden oil. The oil was purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 41 mg (79%) of the title compound as a golden oil. 1H NMR (CDCl3) δ 6.9(s,2H), 6.17(s,1H), 4.30(m,1H), 4.01(s,2H), 3.47(s,3H), 2.30(s,3H), 2.20(s,3H), 2.01(s,6H), 1.70(m,4H), 0.97(t,6H)ppm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)=[O:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH2:20]([NH:27][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)[OH:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a cooled (0° C.) suspension of 2-Bromo-1-(4-octyloxy-phenyl)-ethanone (36.1 g; 110.3 mmol) in EtOH (500 mL) and CHCl3 (100 mL) was added benzylamine (48.2 mL; 441.2 mmol). After 30 minutes the ice-bath was removed and the mixture stirred for another 2 hours at RT. Subsequently the reaction mixture was cooled again to 0° C. and NaBH4 (6.26 g; 165.5 mmol) was added in small portions. The resulting mixture was stirred at 0° C. for 1 hour and thereafter another 4 hours at RT. The reaction mixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 2 N aqueous NaOH. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, EtOAc) to give 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.58 g)
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>>[CH2:30]([S:32]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:34])=[O:33])[CH3:31]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N1CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-[(1-Ethane sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and ethanesulfonyl chloride.