Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:33](OCC(F)(F)F)=[O:34]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][N:15]([CH:33]=[O:34])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=COCC(F)(F)F
Reactant: CCOc1cc(C(CCNO)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC

Procedure:
(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide was prepared by the procedure of Example 7 from N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.6 g, 3.6 mmol) and 2,2,2-trifluoroethyl formate (5 g, 39 mmol) in THF (20 mL) to give a white solid (0.7 g, 41% yield): mp: 81-83° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.34-2.38 (m, 2H, CH2), 2.56-2.65 (m, 1H, CH), 3.39-3.51 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.16 (d, J=17 Hz, 1H, NCHH), 4.55 (d, J=17 Hz, 1H, NCHH), 5.25-5.29 (m, 1H, NCH), 6.93-6.97 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.25 (s, 0.5H, CH), 8.28 (d, J=8 Hz, 1H, Ar), 9.63 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 19.16, 19.21, 28.39, 28.60, 35.94, 43.35, 45.92, 46.26, 46.73, 51.17, 51.92, 55.44, 63.78, 111.97, 112.34, 116.55, 117.54, 117.58, 119.68, 131.54, 132.16, 151.12, 142.28, 147.94, 148.53, 157.36, 161.80, 168.37, 168.53, 174.93; Anal Calcd for C25H31N3O6+0.4 H2O: C, 62.98; H, 6.72; N, 8.81; H2O, 1.51. Found: C, 62.96; H, 6.80; N, 8.84; H2O, 1.48.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC(=O)O)cn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(C)nc1

Procedure:
A stirred mixture of 3-(6-methyl-3-pyridyl)acrylic acid (50.70 g), dry ethanol (350 ml) and concentrated sulphuric acid (25 ml) was heated under reflux for 18 hours and ethanol (~250 ml) was removed by evaporation. The residue was poured into ice-aqueous ammonia and the mixture was extracted with ether. The ether extracts were washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methyl-3-pyridyl)acrylate, m.p. 36°-37°.
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[C:18]3[CH:21]=[C:22]([C:25]#[C:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=[CH:24][C:17]=3[N:16]([CH3:34])[S:15]2(=[O:36])=[O:35])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:34][N:16]1[S:15](=[O:36])(=[O:35])[N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:37])=[O:5])=[CH:12][CH:11]=2)[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([C:25]#[C:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:23]=[CH:24][C:17]1=2
Reactant: CN1c2ccc(C#CCc3ccccc3)cc2C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1c2ccc(C#CCc3ccccc3)cc2C(=O)N(Cc2ccc(C(=O)O)cc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
A solution of 4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4-dihydro-2H-2λ6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic acid tert-butyl ester (0.075 g, 0.15 mmol) was treated with trifluoroacetic acid (5 mL), and the reaction mixture stirred at room temperature for 30 minutes. The solution was evaporated to dryness, the residue dissolved in ethyl acetate, washed with water, brine, and dried over MgSO4, and evaporated. Trituration with ethyl ether afforded a solid that was collected by filtration, washed with ethyl ether, and allowed to air dry under hose vacuum overnight. This afforded 0.015 g of 4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4-dihydro-2H-2λ6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic acid as a light yellow solid (23.2% yield). 1H-NMR (CDCl3); d 8.24 (d, 1H), 8.08-8.05 (d, 2H), 7.69-7.66 (dd, 1H), 7.57-7.55 (d, 2H), 7.38-7.31 (m, 4H), 7.27-7.23 (m, 1H), 7.18-7.16 (d, 1H), 5.16 (s, 2H), 3.34 (s, 3H). MS: M++1=461.1 Da
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[C:13]2[S:12][C:11]([CH2:14]Br)=[CH:10][C:9]=2[C:8]([F:16])=[C:7]([F:17])[CH:6]=1>C1COCC1.C(#N)C>[Br:4][C:5]1[C:13]2[S:12][C:11]([CH2:14][N:2]([CH3:3])[CH3:1])=[CH:10][C:9]=2[C:8]([F:16])=[C:7]([F:17])[CH:6]=1
Reactant: Fc1cc(Br)c2sc(CBr)cc2c1F
Reactant: CNC
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)Cc1cc2c(F)c(F)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetonitrile (1 mL) was added to a solution (0.5 mL) of 2.0 M dimethylamine in THF, and a solution (2 mL) of the compound (121 mg, 0.354 mmol) of Step 1 of Example 65 in acetonitrile was added dropwise under ice-cooling, and stirred at room temperature overnight. The solvent was distilled away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to thus obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([C:18]2[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)[N:3]=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>CN(C=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:3]=[C:4]([C:18]3[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=3)[N:5]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(COc2cc(Cl)nc(-c3nc(C(F)(F)F)cs3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Oc3ccccc3)nc(-c3nc(C(F)(F)F)cs3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution of compound 285 (246 mg, 1 eq.) in anhydrous DMF (5 mL) was added a solution of phenol (69 mg, 1.2 eq.) and NaH 60% in oil (29 mg, 1.2 eq.) in anhydrous DMF (5 mL). The resulting mixture was stirred at room temperature for 3 hrs and concentrated under reduced pressure. The crude material was solubilized in EtOAc (10 mL), and washed sequentially with water and brine. Organics were dried over MgSO4, filtered, and concentrated under reduced pressure to yield compound AH as a beige solid in 100% yield. 1H NMR (CDCl3, 400 MHz) δ 3.82 (s, 3H), 5.48 (s, 2H), 6.01 (s, 1H), 6.83-6.93 (m, 1H), 7.16-7.31 (m; 4H), 4.43 (m, 4H), 7.90 (s, 1H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:41])[CH:7]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=[C:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH:30]=[CH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:22][CH2:21]1)=[O:19])[CH2:8][O:9][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[C:1]([NH:5][C:6](=[O:41])[CH:7]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=[C:26]2[C:27]3[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=3[CH:29]=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=3)[CH2:22][CH2:21]1)=[O:19])[CH2:8][OH:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)C(CO)NC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
113 mg (0.197 mmol) of N-[2-(t-butylamino)-1-({[t-butyl(dimethyl)-silyl]oxy}methyl)-2-oxoethyl]-4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinecarboxamide was dissolved in 3 ml of tetrahydrofuran. 0.22 ml of 1 M tetrabutylammonium fluoride/tetrahydrofuran solution was added to the obtained solution, and they were stirred for 30 minutes. After the purification by the silica gel chromatography (hexane:ethyl acetate=9:1 to 3:2), the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)(=[O:4])=[O:3].[NH2:15][C@@H:16]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=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(Cl)Cl>[F:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([F:38])[CH:34]=1)[CH2:30][C@H:16]([NH:15][C:12]([CH:9]1[CH2:8][CH2:7][CH:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:11][CH2:10]1)=[O:14])[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CS(=O)(=O)CC1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)C2CCC(CS(C)(=O)=O)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.4 %

Procedure:
To a stirred solution of acid from step 6 (100 mg, 0.5 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (190 mg, 0.5 mmol), and HATU (175 mg, 0.5 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (280 μL, 1.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 95:5 to 92:8 methylene chloride/methanol) provided the title compound (60 mg): mp 45-50° C.; ESI MS m/z 537 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([C:21]([OH:24])([CH3:23])[CH3:22])[C:13]([NH:15][CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:14])=O)(C)(C)C.Cl.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49]([OH:51])=O)[CH2:43][C:44]1[N:45]=[CH:46][S:47][CH:48]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49]([NH:8][C@@H:9]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([C:21]([OH:24])([CH3:22])[CH3:23])[C:13]([NH:15][CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:14])=[O:51])[CH2:43][C:44]1[N:45]=[CH:46][S:47][CH:48]=1)=[O:40])([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A mixture of 530 mg (1.16 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-[2(S)-methylbutyl]hexanamide (prepared as described in Preparation 7) in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the solvent was again removed by distillation under reduced pressure. This operation was repeated in total three times, and then the residue was dried under vacuum for 8 hours. The dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and then 350 mg (1.29 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the resulting suspension. Subsequently, 0.21 ml (1.38 mmoles) of 95% diethyl cyanophosphate (i.e. diethyl cyanophosphate of purity about 95%) and 0.36 ml (2.58 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling, and under an atmosphere of nitrogen. The mixture was stirred for 6 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), to give 650 mg (yield 92%) of the title compound as white crystals, melting at 190°-193° C.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:4]1[NH:5]2.[C:17]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[CH3:17][C:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C@H:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:4]1[NH:5]2
Reactant: c1ccc2c(c1)CC1Nc3ccccc3C21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cc1cccc2c1[C@H]1c3ccccc3C[C@H]1N2
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A mixture of 0.6 g (0.00289 mol) of 5,5a, 6,10b-tetrahydroindeno[2,1-b]indole, 0.9 g (0.00723 mol) of K2CO3 and 1.03 g (0.00723 mol) of methyl iodide in 10 ml of acetonitrile was stirred for over the night at room temperature. The resulting mixture was filtered and evaporated. The resulting residue was dissolved in ether and then washed twice with water. Drying (Na2SO4) and evaporation gave 0.25 g (39%) of the title compound. 1H NMR (CDCl3) δ, 2.78 (3H, s), 3.2 (2H, d), 4.3 (1H, m) 4.66 (1H, d), 6.37 (1H, d), 6.68(1H, t), 7.06 (1H, t), 7.13-7.18 (2H, m),7.22-7.26 (1H, m) 7.3-7.37 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>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>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(F)cc1
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: O
Solvent: C1COCCO1
Product: CC(C)Cn1nc2c(-c3ccc(F)cc3)c(-c3ccc(F)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 66.9 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-fluorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (33 mg, 0.087) as a pale yellow solid. MS: [M+H]+=380.
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[CH:16][CH:15]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(Br)CO
Reactant: Oc1ccc(COc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CO)Oc1ccc(COc2ccc(Cl)cc2)cc1
Reaction time: 12 h

Procedure:
A solution of 15.3 g. of 2-bromo-2-methylpropanol in 50 ml. of acetone is added slowly to a stirred mixture consisting of 23.45 g. of 4-p-chlorophenoxymethyl-phenol, 13.8 g. of K2CO3 an 80 ml. of acetone. The mixture is boiled for 12 hours while stirring and then filtered and evaporated to give 2-[4-(4-chlorophenoxymethyl)-phenoxy]-2-methyl-propanol, m.p. 67°-70° C.
Reaction SMILES: [O:1]=[C:2]([C:6]([CH2:25][O:26][Si](CC)(CC)CC)([CH2:16][O:17][Si](CC)(CC)CC)[CH2:7][O:8][Si](CC)(CC)CC)[CH2:3][C:4]#[N:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:26][CH2:25][C:6]([CH2:7][OH:8])([CH2:16][OH:17])[C:2](=[O:1])[CH2:3][C:4]#[N:5]
Reactant: CC[Si](CC)(CC)OCC(CO[Si](CC)(CC)CC)(CO[Si](CC)(CC)CC)C(=O)CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)C(CO)(CO)CO

Procedure:
To a stirred solution of 3-oxo-5-(triethylsilyloxy)-4,4-bis((triethylsilyloxy)methyl)pentanenitrile (1 equivalent) in anhydrous THF at 0° C. is added tetrabutylammonium fluoride (1-5 equivalents) then stirring is continued at rt until the reaction is substantially complete as monitored by LCMS or TLC. Water is added followed by extraction with EtOAc. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 5-hydroxy-4,4-bis(hydroxymethyl)-3-oxopentanenitrile.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=[N:4][C:3]=1[N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:3]3[N:4]=[N:5][C:6]([CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: Cc1c(Cc2cccnc2)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4cccnc4)c(C)c3C)C[C@H]2C)cn1
Yield: 5.9 %

Procedure:
4,5-Dimethyl-3-((R)-3-methyl-piperazin-1-yl)-6-pyridin-3-ylmethyl-pyridazine (350 mg, 1.18 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (243.7 mg, 1.41 mmol) are added to a microwave vial followed by NMP (7 mL) and triethylamine (0.49 mL, 3.54 mmol). The vial is sealed and irradiated in the microwave at 145° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2) to afford the title compound (30 mg, 6%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][N:15](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[OH:13][CH2:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[C:14]#[N:15]
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(CO)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
(3-Bromo-5-trifluoromethyl-phenyl)-methanol (33.9 g) is dissolved in N,N-dimethylformamide (400 mL) and thereto are added zinc(II) cyanide (16.39 g) and tetrakis(triphenylphosphine)palladium (7.68 g) and the mixture is heated under nitrogen atmosphere at 120° C. for 2 hours. The reaction solution is allowed to cool to room temperature, and filtered through Celite™, and the filtrate is concentrated under reduced pressure. Thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3-hydroxymethyl-5-trifluoromethyl-benzonitrile (23.4 g). NMR (CDCl3): 2.09 (1H, t), 4.85 (2H, d), 7.83 (1H, s), 7.87 (2H, s)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:21][CH2:20][CH2:19][O:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([N:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:28])=[CH:25][N:24]=1>>[CH3:14][N:13]([CH3:15])[C:11]([C:9]1[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)[C:6]2[N:7]=[C:2]([NH:22][C:23]3[CH:45]=[CH:44][C:26]([C:27]([N:29]4[CH2:30][CH:31]5[N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH:34]([CH2:33][CH2:32]5)[CH2:35]4)=[O:28])=[CH:25][N:24]=3)[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCOC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCOC1
Yield: 25.4 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (80 mg, 0.26 mmole) was combined with tert-butyl 3-(6-aminonicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (82 mg, 0.26 mmole) which gave tert-butyl 3-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg) in 25% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.84 (s, 1H), 8.72-8.65 (m, 1H), 8.42 (m, 1H), 7.89-7.82 (m, 1H), 6.56 (s, 1H), 4.63-4.52 (m, 1H), 4.52-4.41 (m, 1H), 4.26 (br, 2H), 4.08-3.96 (m, 2H), 3.70-3.49 (m, 3H), 3.16 (S, 6H), 3.23-3.02 (m, 1H), 3.03-2.88 (m, 1H), 2.18-2.07 (m, 1H), 2.02-1.57 (m, 7H), 1.51 (s, 9H). HR-MS m/z 605.3201 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:14])=[N:10][O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18]N=1>>[CH:16]1([C:12](=[O:11])[CH2:8][CH2:5][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:9]([CH3:14])=[N:10][O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Brc1ccccn1
Reactant: Cc1noc(C)c1-c1ccc(Br)cc1
Product: Cc1noc(C)c1-c1ccc(CCC(=O)C2CCCC2)cc1

Procedure:
The title compound was prepared as described in Step 1 of Example A(82), where 4-(4-Bromo-phenyl)-3,5-dimethyl-isoxazole from Step 1 of Example A(18), was substituted for 2-Bromopyridine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[C:23]([CH3:32])=[CH:24][C:25]([CH3:31])=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([CH3:31])=[CH:24][C:23]=2[CH3:32])=[CH:9][C:8]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cccnn2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnn2)cc1Nc1cc([N+](=O)[O-])c(C)cc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.09 g (3.93 mmol) of the compound of Example 80A and 996 mg (4.33 mmol) of 5-bromo-2,4-dimethylnitrobenzene gave, after 3 h of heating under reflux, a crude product which was purified by chromatography on a Biotage system (100 g Snap column; mobile phase gradient ethyl acetate/0-8% methanol). This gave 1.38 g (77% of theory) of the title compound.