Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CCN(CC)CC.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH3:37][C:38]1([CH3:66])[CH2:43][CH2:42][C:41]([C:44]2[N:49]=[C:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:47]=[CH:46][C:45]=2[NH:56][C:57]([C:59]2[NH:60][CH:61]=[C:62]([C:64]#[N:65])[N:63]=2)=[O:58])=[CH:40][CH2:39]1>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([N:53]1[CH2:54][CH2:55][CH:50]([C:48]2[CH:47]=[CH:46][C:45]([NH:56][C:57]([C:59]3[NH:60][CH:61]=[C:62]([C:64]#[N:65])[N:63]=3)=[O:58])=[C:44]([C:41]3[CH2:42][CH2:43][C:38]([CH3:66])([CH3:37])[CH2:39][CH:40]=3)[N:49]=2)[CH2:51][CH2:52]1)=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CC1(C)CC=C(c2nc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1
Yield: 42.8 %

Procedure:
A suspension of 20.9 mg (0.203 mmol) N,N-dimethylglycine in 4 mL CH2Cl2 was treated with 49.8 mg (0.197 mmol) bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) and 75 μL (0.54 mmol) Et3N at room temperature for 1 h. The mixture was then treated with 70.0 mg (0.135 mmol) 4-cyano-1H-imidazole-2-carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetate (as prepared in Example 54, step(f)) at room temperature for 18 h. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min to afford 34.9 mg (53%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.38 (d, 1H, J=8.4 Hz), 8.05 (s, 1H), 7.33 (d, 1H, J=8.4 Hz), 6.05-5.98 (m, 1H), 4.68 (d, 1H, J=15.2 Hz), 3.82 (d, 1H, J=15.2 Hz), 3.16-3.05 (m, 1H), 3.01-2.94 (m, 6H), 2.52-2.40 (m, 2H), 2.39 (s, 6H), 2.17-2.10 (m, 2H), 2.09-1.87 (m, 2H), 1.67-1.59 (m, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H35N7O2, 490.3 (M+H). found 490.4.
Reaction SMILES: [CH3:1][N:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].B(F)(F)F.CCOCC.[Li]CCCC.Cl[P:30]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[CH:37]1([P:30]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[C:5]2[C-:4]([N:2]([CH3:3])[CH3:1])[CH:8]=[CH:7][CH:6]=2)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CN(C)[c-]1cccc1
Agent: [Fe+2]
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)[c-]1cccc1P(C1CCCCC1)C1CCCCC1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
In a dry round bottom flask under argon, an ice-cold solution of dimethylaminoferrocene 11 (229 mg, 1.00 mmol) in THF (10 mL) was treated with BF3.OEt2 (0.13 mL, 1.05 mmol). After 15 min, the yellow solution was cooled to −40° C. and n-BuLi (0.46 mL of 2.40 M solution in hexanes, 1.10 mmol) was added by syringe to give an orange-red solution that was stirred for 1 h before ClPCy2 (0.24 mL, 1.10 mmol) was added and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with Et2O (10 mL) and worked up with saturated aqueous NaHCO3 solution (10 mL). The organic layer was washed with H2O (1×10 mL), brine (1×10 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was redissolved in pentane and chromatographed on silica gel (25 mL), eluting with 95:5 pentane/Et2O to give 397 mg (77%) of the desired aminophosphine 12j as a moderately air-sensitive viscous orange oil. Rf (SiO2, 9:1 hex/EtOAc) 0.50; IR (CHCl3): vmax 2920, 2848, 1489, 1446 cm−1, 31P NMR (121 MHz, acetone-d6): δ −12.3; 1H NMR (300 MHz, acetone-d6): δ 4.22 (s, 5H), 4.15 (t, 1H, J=1.1 Hz), 4.04 (t, 1H, J=2.3 Hz), 3.92 (t, 1H, J=1.7 Hz), 2.75 (s, 6H), 2.49-2.41 (m, 1H), 2.00-1.93 (m, 1H), 1.92-1.81 (m, 3H), 1.77-1.67 (m, 2H), 1.67-1.61 (m, 1H), 1.61-1.52 (m, 3H), 1.50-1.20 (m, 7H), 1.20-1.06 (m, 2H), 1.06-0.97 (m, 1H), 0.90-0.79 (m, 1H); 13C NMR (75.5 MHz, acetone-d6) δ 118.0 (d, J13C-31P=14.0 Hz), 67.5, 66.6 (d, J13C31P=3.4 Hz), 63.3 (d, J13C-31P=25.3 Hz), 63.2, 61.3 (d, J13C-31P=1.5 Hz), 43.9 (d, J13C-31P=13.2 Hz), 35.0 (d, J13C-31P=15.9 Hz), 33.2 (d, J13C-31P=13.2 Hz), 32.2 (d, J13C-31P=20.6 Hz), 30.2 (d, J13C-31P=15.9 Hz), 29.5 (d, J13C-31P=10.8 Hz), 29.0, 27.3 (d, J13C-31P=11.8 Hz), 27.2 (d, J13C-31P=6.5 Hz), 27.0 (d, J13C-31P=12.8 Hz), 26.8 (d, J13C-31P=8.3 Hz), 26.3 (d, J13C-31P=15.5 Hz). EIMS (m/z (%)): 425 (M+, 87), 130 (62), 55 (100), 41 (94); HRMS (EI; m/z): calcd for C24H36NP56Fe 425.1936. Found 425.1934.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[N:24]([CH2:25][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])([CH3:28])[CH3:27])[C:23]([CH2:34][O:35][CH2:36][CH3:37])=[N:22][C:16]=3[CH:17]=[N+:18]([O-])[C:19]=2[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>ClCCl.C(Cl)(Cl)Cl.CO>[NH2:2][C:17]1[C:16]2[N:22]=[C:23]([CH2:34][O:35][CH2:36][CH3:37])[N:24]([CH2:25][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])([CH3:28])[CH3:27])[C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:20][C:19]=2[N:18]=1
Reactant: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 1 h

Procedure:
Concentrated ammonium hydroxide (3 to 4 mL) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (1.75 g, 3.51 mmol) in dichloromethane (35 mL) with rapid stirring. p-Toluenesulfonyl chloride (670 mg, 3.51 mmol) was added. The reaction was stirred for one hour; a precipitate formed. Water (100 mL) was added, and the dichloromethane was removed under reduced pressure. Dichloromethane (5 mL) was then added with rapid stirring, and the resulting powder was isolated by filtration and dissolved in 90:10 chloroform:methanol (200 mL). The resulting solution was concentrated under reduced pressure, and the residue was triturated with hot propyl acetate (50 mL), isolated by filtration, and dried under reduced pressure to provide 1.45 g of N-[2-(4-amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a tan powder.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)Cl.[C:32](Cl)(=[O:41])[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C1C=CN=CC=1.CCOCC>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([C:32](=[O:41])[CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
1.42 grams (5.15 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 1.56 grams (15.45 millimoles0 of triethylamine, 0.06 gram (0.51 millimoles) of 4-dimethylaminopyridine and 25 milliliters of methylene chloride were stirred together for 5 minutes and to the stirred solution, 0.86 gram (5.15 millimole) of cinnamoyl chloride was added in one portion. The resulting mixture was stirred for 0.5 hour at room temperature, then diluted with 200 milliliters of ether and the ethereal solution washed successively with two 200 milliliter portions of 2N hydrochloric acid, one 200 milliliter portion of sodium bicarbonate solution and one 300 milliliter portion of brine. The washed solution was dried over magnesium sulfate, and the solvent vaporized in vacuo from the dried solution to obtain as residue 1.6 grams of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamoylpiperidine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:25][CH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.O.C(#N)C>CN1C(=O)CCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([NH:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH3:34])[CH3:35])=[O:32])=[CH:36][CH:37]=4)[N:3]=[C:4]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]=3[N:11]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NCC(F)(F)F)c3n2)cc1
Reactant: CN(C)C(=O)c1ccc(CN)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)C(=O)c1ccc(CNc2nc(NCC(F)(F)F)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Reaction time: 1 h
Yield: 15 %

Procedure:
[2-Chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-(2,2,2-trifluoroethyl)-amine (100 mg, 0.28 mmol), 4-aminomethyl-N,N-dimethyl-benzamide (100 mg, 0.56 mmol) and diisopropylethylamine (0.097 mL, 0.56 mmol) were suspended in NMP (1.5 mL), sealed and heated by microwave to 140 deg C. for 1 h. After cooling the reaction mixture was added dropwise to a stirring mixture of water/acetonitrile (8 mL, 3:1) to afford a yellow precipitate. The solid was filtered, washed with water, dissolved in hot dioxane and concentrated onto silica gel. Purification by flash chromatography (0-10%, EtOH (containing 11% saturated aqueous ammonium hydroxide) in dichloromethane) to afford 21 mg (15%) of the desired product as a white solid. MS (m/z) 499.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:4](=[O:25])[NH:3]1.[CH:26](=O)[CH3:27].[BH4-].[Na+]>FC(F)(F)C(O)=O.CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH2:26][CH3:27])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[C:4](=[O:25])[NH:3]1
Reactant: NS(=O)(=O)c1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCNS(=O)(=O)c1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-{[(1,3-Dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-methyl}-benzenesulfonamide (35.7 mg, 0.1 mmol) in Trifluoroacetic acid (250 μL) is added acetaldehyde (16.3 μL, 0.3 mmol) and sodium borohydride (11.4 mg, 0.3 mmol). The reaction mixture is shaken at ambient temperature for 18 hours. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH3:14])[NH:12][C:11](=[O:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[C:18]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([N:12]2[C@@H:13]([CH3:14])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C:11]2=[O:15])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: Cc1c(Br)ccc(C#N)c1Cl
Reactant: C[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(N2C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-methylpyrrolidin-2-one (495 mg), 4-bromo-2-chloro-3-methylbenzonitrile (500 mg), cesium carbonate (1.05 g), tris(dibenzylideneacetone)dipalladium(0) (99 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (124 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 505 mg, 74%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1([CH3:25])[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([CH3:24])[C:15]([CH3:23])=[C:16]([OH:22])[C:17]=2[CH3:21])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH2:1]([NH:8][C:9](=[O:10])[C:11]([OH:26])([CH3:25])[CH2:20][CH2:19][C:18]1[C:13](=[O:12])[C:14]([CH3:24])=[C:15]([CH3:23])[C:16](=[O:22])[C:17]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCc1ccccc1)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCc2ccccc2)=C(C)C1=O
Yield: 87.9 %

Procedure:
Oxidation as described in protocol B, using 130 mg (0.383 mmol) of N-benzyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 441 mg CAN (0.805 mmol) yielded 119.7 mg of N-benzyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow foam.
Reaction SMILES: C[O-].[Na+].[C:4](OC)(=O)[CH2:5][C:6]([O:8]C)=[O:7].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=C(Br)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.BrC1C=CC=CC=1.[OH-].[Na+]>[Cu]Br.[Cu]I.O.COCCOC>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:4]([CH2:5][C:6]([OH:8])=[O:7])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: COC(=O)CC(=O)OC
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]Br
Agent: [Cu]I
Agent: C[O-]
Solvent: Brc1ccccc1
Solvent: O
Solvent: COCCOC
Product: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 69 °C
Reaction time: 1.83 h
Yield: 89 %

Procedure:
550 ml of ethylene glycol dimethyl ether were initially charged and, under nitrogen, 91 g of sodium methoxide (solid) were introduced, giving, without any change in temperature, a white suspension which was readily stirrable. The mixture was heated to 69° C. and 237.6 g of dimethyl malonate were added dropwise over a period of 30 minutes, during which the mixture began to boil under reflux (internal temperature 74° C.) and a stirrable white slurry was formed. After cooling to 54° C., 35.2 g of copper(I) bromide (fine powder) and 35.2 g of copper(I) iodide (fine powder) were added, and the mixture was then again heated at the boil under reflux. Over a period of 110 minutes, 344 g of 3,5-bis-(trifluoromethyl)-bromobenzene were added dropwise, and a gentle stream of waste gas was observed (partial de-methoxycarbonylation). After 15 hours and 40 minutes (conversion monitored by GC) at reflux (85° C.), a further 10 g of copper(I) bromide and a further 10 g of copper(I) iodide were added. After a further 5 hours under reflux at 86° C. (conversion monitored by GC; at least 90% conversion of the bromobenzene employed), 400 g of 45% by weight strength aqueous sodium hydroxide solution were added dropwise at 86° C. (reflux) over a period of 15 minutes and the mixture was kept at reflux at this temperature for a further 4 hours, during which a gentle evolution of waste gas took place. GC analysis then showed that no more ester was present. With stirring, 1000 ml of water were added and the precipitate was allowed to settle. Undissolved particles were then substantially decanted off over a Nutsche and the remaining content of the flask was suspended in 100 ml of 2 N aqueous sodium hydroxide solution and filtered off with suction over the Nutsche. The resulting two-phase filtrate was concentrated at 20 mbar (1350 ml of distillate) and diluted again with 1000 ml of water. Organic impurities were extracted using 30 ml of toluene (1.4 g of residue on concentration using a rotary evaporator) and the aqueous phase was poured into 920 g of 24% by weight strength aqueous sulphuric acid (18-24° C.), which resulted in strong foaming (pH=1). The resulting precipitate was filtered off with suction, washed with a little water until neutral and dried at 60° C. overnight. This gave 284 g of a beige powder, corresponding to a yield of 89% of theory.
Reaction SMILES: C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1.[C:30](=[O:32])=[O:31]>O1CCCC1>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([CH3:29])=[CH:27][C:28]=1[C:30]([OH:32])=[O:31]
Reactant: O=C=O
Reactant: Cc1ccc(Cl)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cnc(Cl)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5M solution of butyllithium in hexane (9.4 mL, 23.5 mmol) was added to tetrahydrofuran (50 mL) and the mixture cooled to −78° C. The mixture was treated with 2,2,6,6-tetramethylpiperidine (4.4 mL, 26.0 mmol) and stirred at −78° C. for 30 minutes. The reaction mixture was then treated with 2-chloro-5-methylpyridine (3.00 g, 23.5 mmol) and stirred at −78° C. for a further 2.5 hours. The reaction mixture was poured into a beaker of dry ice and warmed to room temperature on a water bath, then extracted into water. The mixture was acidified with 2M hydrochloric acid, extracted into ether and washed with water (×2) and brine. The solution was dried over magnesium sulphate to yield the title product as a yellow solid, 1.65 g.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([NH2:15])(=O)C.C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC.Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cu]Cl.C(OCC)(=O)C.O.C1(C)C(C)=CC=CC=1>[NH2:15][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(N)=O
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 145 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
To a mixture of 2,6-dichloronicotinic acid (36 g), acetamide (80 g), potassium carbonate (78 g), copper(I) chloride (0.93 g), and xylene (80 mL) was added tris(2-(2-methoxyethoxy)ethyl)amine (3.0 mL), which was stirred overnight at 145° C. The reaction mixture was cooled to room temperature, after which copper(I) chloride (0.46 g) was added to the reaction mixture at the same temperature, and then stirred overnight at 145° C. The reaction mixture was cooled to 105° C., after which water (100 mL) was added at the same temperature, and then stirred for 1 hour at the same temperature. The reaction mixture was cooled to room temperature, 5N hydrochloric acid (150 mL) was added thereto at the same temperature, and then the reaction mixture was neutralized with an aqueous citric acid solution. Ethyl acetate was added to the reaction mixture, which was filtered through Celite. The organic layer was washed with saturated brine, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), after which recrystallization was performed from an ethyl acetate-hexane system to obtain the titled compound (1.4 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+].CCOCC.[OH-].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.O1CCCC1>[C:21]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
N-benzoylphenylalaninol is synthesized by following steps of: i) suspending 1 mole (163 g) of L-phenylalaninol to 1 L of tetrahydrofuran, ii) adding 2.5 mole (100 g) of NaBH4 to the solution, iii) dropping 1.25 mole of ether-diluted sulfuric acid (66 ml, total volume 200 ml) to the solution at 0° C., iv) after reacting the solution for 12 hours at room temperature, adding 200 ml of methanol slowly, v) after adding 1 L of 5N-NaOH, evaporating organic solvent and refluxing for 3 hours, vi) after cooling to room temperature, adding 1 L of methylenechloride to the solution, vii) adding 1 mole of benzoylchloride to the solution slowly at 0° C., viii) after finishing the reaction, filtering the reaction mixture, ix) washing the product with hot water three times, and x) obtaining 207 g (81%) of N-benzoylphenylalaninol after drying the product.
Reaction SMILES: C(OC(=O)[N:7]([C:39]1[CH:40]=[N:41][C:42](Cl)=[CH:43][CH:44]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:16]2[C:24]3[C:23]([CH:25]4[CH2:27][CH2:26]4)=[N:22][CH:21]=[N:20][C:19]=3[N:18]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:17]=2)[OH:15])=[C:10]([F:38])[N:9]=1)(C)(C)C.[CH:47]1([Mg]Br)[CH2:49][CH2:48]1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:47]1([C:42]2[N:41]=[CH:40][C:39]([NH:7][C:8]3[N:9]=[C:10]([F:38])[C:11]([CH:14]([C:16]4[C:24]5[C:23]([CH:25]6[CH2:26][CH2:27]6)=[N:22][CH:21]=[N:20][C:19]=5[N:18]([Si:28]([CH:32]([CH3:33])[CH3:34])([CH:35]([CH3:36])[CH3:37])[CH:29]([CH3:31])[CH3:30])[CH:17]=4)[OH:15])=[CH:12][CH:13]=3)=[CH:44][CH:43]=2)[CH2:49][CH2:48]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc2F)c2c(C3CC3)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(Nc3ccc(C4CC4)nc3)nc2F)c2c(C3CC3)ncnc21
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To (6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-carbamic acid tert-butyl ester (81, 0.51 g, 0.77 mmol) in 12 mL of toluene, [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.13 g, 0.17 mmol) is added under nitrogen and the reaction stirred for 5 minutes. Cyclopropylmagnesium bromide (17, 15.29 mL, 0.50 M in tetrahydrofuran, 7.65 mmol) is added slowly and the reaction is heated at 65° C. for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (82, 400 mg).
Reaction SMILES: N.C([O:9][CH2:10][CH2:11][C:12]12[O:19][CH2:18][C:15]([CH3:20])([CH2:16][O:17]1)[CH2:14][O:13]2)C1C=CC=CC=1.[Na].[Cl-].[NH4+]>O1CCCC1>[OH:9][CH2:10][CH2:11][C:12]12[O:13][CH2:14][C:15]([CH3:20])([CH2:16][O:17]1)[CH2:18][O:19]2
Reactant: CC12COC(CCOCc3ccccc3)(OC1)OC2
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC12COC(CCO)(OC1)OC2
Yield: 60 %

Procedure:
To liquid ammonia (35 ml) was added, under an argon atmosphere, a solution of 1-(2-Benzyloxyethyl)-4-methyl-2,6,7-trioxabicyclo-[2.2.2]octane (3.54 g) in anhydrous tetrahydrofuran (8 ml). Metallic sodium (500 mg) was then added thereto, and the resultant mixture was stirred for 3 hours at −78° C. After ammonium chloride was added to the reaction mixture, ammonia was evaporated, and tetrahydrofuran was evaporated under reduced pressure. The residue was washed with ether, and the resultant solid was added to saturated brine and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 1-(2-hydroxyethyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (1.4 g) as a pale yellow oil.