Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C(N(CC)C(C)C)(C)C.[P:43]([O-:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46]>C(O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[C:12]([C:13]([CH3:30])([CH3:29])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:31]=[CH:32][C:2]([F:1])=[CH:3][C:4]=1[P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: CCOP([O-])OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(OCC)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 80 °C
Yield: 51.3 %

Procedure:
A solution of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.200 g, 0.35 mmol) and triphenylphosphine (0.020 mg) in ethanol (5 ml) was flushed with argon and then treated with N,N-diisopropylethylamine (0.25 ml, 1.4 mmol), palladium(11) acetate (0.020 g) and diethyl phosphite (0.15 ml, 1.16 mmol). The reaction mixture was then sealed and heated at 80° C. for 18 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine, then dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of acetonitrile in dichloromethane) gave 0.103 g (51% yield) of the title compound as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.36 (6H, t, J=6.6 Hz, 2×CH3), 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.08-4.22 (4H, m, 2×OCH2), 4.78 (2H, d, J=6.6 Hz, NCH2), 5.29 (2H, s, OCH2), 7.21 (1H, m, aromatic), 7.29-7.34 (3H, m, aromatics), 7.45-7.52 (3H, m, aromatics), 7.65-7.72 (1H, m, aromatic), 8.67 (1H, broad t, NH). HRMS (ESI+) calculated for C28H34FN3O7P [M+H+]: 574.2118; found: 574.2126.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([O-:7])([O-])=O.[Na+].[Na+].O1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15]C>CCOCC>[O:7]1[CH2:4][CH2:14][CH2:13][C@@H:12]1[CH2:11][NH:15][C:2]#[N:1]
Reactant: O=C([O-])[O-]
Reactant: N#CBr
Reactant: CN[C@H]1CCCO1
Agent: [Na+]
Solvent: CCOCC
Product: N#CNC[C@H]1CCCO1
Reaction time: 1.5 h
Yield: 178.8 %

Procedure:
To a stirred mixture of cyanogen bromide (2.2 g, 20.8 mmol) and anhydrous Na2CO3 (4.2 g, 39.6 mmol) in dry ether (30 mL) at about −20 to about −10° C. was added (R)-(tetrahydro-furan-2-yl)-methylamine (Aldrich) (2.0 g, 9.8 mmol) over 10 minutes. Stirring was continued for an additional 1.5 hours at about −20 to about −10° C. Then the mixture was filtered and concentrated to provide 2.21 g of the title product. MS (DCI/NH3) m/z 127 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN(C)[CH:37]=[C:38]([N:44]1[CH:48]=[C:47]([C:49]#[N:50])[N:46]=[N:45]1)[C:39](OCC)=[O:40]>O>[F:11][C:12]1([F:18])[CH2:17][CH2:16][N:15]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:39](=[O:40])[C:38]([N:44]4[CH:48]=[C:47]([C:49]#[N:50])[N:46]=[N:45]4)=[CH:37][NH:9]3)[CH:7]=2)[CH2:14][CH2:13]1
Reactant: FC1(F)CCNCC1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1
Reactant: NNc1cc(Cl)ncn1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCC(F)(F)CC4)ncn3)c2=O)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (1.4 mmol) of the compound from Example 11A, 262 mg (1.7 mmol) of 4,4-difluoropiperidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 325 mg (1.4 mmol) of the compound from Example 7A, the reaction mixture is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 34 mg (7% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[C:22]([F:27])=[CH:21][C:20]=2[N+:28]([O-])=O)[C:12]=1[F:31])=[O:8].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C1COCC1.CCOC(C)=O>[NH2:28][C:20]1[CH:21]=[C:22]([F:27])[C:23]([C:25]#[N:26])=[CH:24][C:19]=1[O:18][C:13]1[C:12]([F:31])=[C:11]([CH2:10][NH:9][C:7]([C:6]2[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:38])[CH3:39])[CH:4]=[N:3][C:2]=2[Cl:1])=[O:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2[N+](=O)[O-])c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2N)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(5-cyano-4-fluoro-2-nitrophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (450 mg, 0.752 mmol) in THF (3 ml) was added sodium hydrosulfite (85% tech.) (924 mg, 4.51 mmol) in solution of Water (6.00 ml) and the reaction mixture was stirred at 60° C. for one hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (386 mg, 0.679 mmol, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (t, 1H), 7.98 (s, 1H), 7.39-7.49 (m, 1H), 7.34 (t, 1H), 6.70 (s, 2H), 6.56-6.68 (m, 2H), 5.49 (s, 2H), 4.47 (d, 2H), 3.39 (t, 2H), 0.75 (t, 2H), −0.08 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]([N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][CH:4]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]([N:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])(=[O:32])=[O:31]
Reactant: CN(C(=O)CC(CCO)c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccccc1
Yield: 100.3 %

Procedure:
Beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (5.0 g) in CH2Cl2 (100 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (2.23 g), and methanesulfonyl chloride (2.53 g). After two hours the reaction mixture was washed with water(3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (6.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O.N1C=CC=C[CH:17]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2-(5-bromopyridin-3-yl)acetic acid (5.00 g, 23.14 mmol) in methanol (55 mL) at 0° C. was added thionyl chloride (2.196 mL, 30.1 mmol) slowly, pyridine (2.434 mL, 30.1 mmol) was added slowly after and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was diluted with water and extracted with ethyl acetate, the organics was washed with brine, dried over magnesium sulfate, filtered and concentrated. Biotage purification (35% EtOAc/Hex) gave title compound (4.73 g, 20.6 mmol, 89% yield). 1H-NMR (CDCl3, 500 MHz) δ 8.63 (d, J=2.14 Hz, 1H), 8.47 (d, J=1.83 Hz, 1H), 7.84 (dd, J=2.14, 1.83 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 2H). Mass spec.: 230.9 (MH)+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)=[O:9].[ClH:23]>CC(O)C>[ClH:23].[O:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:23].[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:7]
Reactant: CC(C)(C)N
Reactant: O=C(CBr)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)c1ccccc1
Product: CC(C)(C)NCC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Tert-butylamine (15 ml) was added with stirring to a solution of 2-bromo-4′-phenoxyacetophenone (12.7 g, prepared by bromination of 4′-phenoxyacetophenone according to Tetrahedron Letters, 1993, 34, 3177) in propan-2-ol and the mixture heated at 80° C. for 3 hours. The mixture was cooled to 0° C. and concentrated hydrochloric acid (10 ml) added. The suspension was stirred at ambient temperature for 18 hours and the solid collected by filtration to give 4′-phenoxy-2-(tert-butylamino)acetophenone hydrochloride (3.75 g), m.p. 210-212° C. butylamino)acetophenone hydrochloride (3.75 g), m.p. 210-212° C.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:30]=[CH:29][C:20]([CH:21]=[C:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:19][CH:18]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:30]=[CH:29][C:20]([CH:21]=[C:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:19][CH:18]=3)[N:14]=2)[NH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C4SC(=O)NC4=O)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C4SC(=O)NC4=O)cc3)nc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
In a 35 ml vial, 5-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)thiazolidine-2,4-dione (0.100 g, 0.0001 mole) was taken in 8 ml CH2Cl2 and cooled to 0° C. under N2 atm. TFA (2 ml, 0.0268 mole) was added dropwise at 0° C. and the reaction mixture was stirred for 16 h at room temperature. After completion of the reaction, solvent was evaporated under reduced pressure from the reaction mixture and saturated NaHCO3 solution was added dropwise to make Ph basic. The solid that precipitated out was washed with water and pentane and 0.050 g of the solid was taken up in ethanol (20 ml) and NaOAc.3H2O (0.246 g, 0.0018 mole) was added. The reaction mixture was stirred at room temperature for 16 hr. Ethanol was evaporated under reduced pressure and the solid was washed with water and pentane. The crude compound was purified by triturating with pentane to yield 0.018 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: C1CCNC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N1CCCC1
Temperature: 85 °C
Reaction time: 13 h
Yield: 83.1 %

Procedure:
A solution of methyl [4-chloro-6-methyl-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.45 g, 1.3 mmol) and pyrrolidine (0.13 mL, 1.6 mmol) in DMF (10 mL) at room temperature was treated with triethylamine (0.22 mL, 1.6 mmol) and the resulting mixture was stirred at 85° C. for 13 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts was washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed over silica gel eluting with 50% EtOAc in CH2Cl2 to give methyl [4-methyl-2-(4-nitrobenzyl)-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate (0.40 g, 80% yield) as a white powder.
Reaction SMILES: OO.O[Li].O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:19]=[O:20])[CH2:14][NH:15][C:16](=[O:18])[O-:17])=[CH:9][CH:8]=1.CO[C:23]1C=C(OC)C=[CH:27][C:24]=1[CH:25]=O.[O-:33]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:24]([O:18][C:16]([NH:15][CH2:14][C@H:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)[C:19]([OH:33])=[O:20])=[O:17])([CH3:27])([CH3:25])[CH3:23]
Reactant: O=S([O-])[O-]
Reactant: O=CC(CNC(=O)[O-])c1ccc(Cl)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 94.2 %

Procedure:
35% H2O2 (0.240 mL, 2.91 mmol) was added to a solution of LiOH—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes, and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-(R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The ice bath was allowed to slowly warm, and the reaction mixture was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added. The mixture was stirred for 5 minutes, and then warmed to room temperature and stirred an additional 20 minutes. The reaction mixture was then transferred to a reparatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M-BOC+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[O:15]CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(O)c1

Procedure:
To a solution of [4-methyl-2-(phenylmethoxy)phenyl]acetic acid tert-butyl ester (10.67 g, 34.2 mmol) in 125 ml of ethanol was added palladium block (200 mg), the mixture was hydrogenated (using a hydrogen balloon) at 30° C. for 10 hr. After the starting material disappeared completely (detected by TLC), the solid was filtered off, and the solvent was evaporated to give a crude product of (2-hydroxy-4-methylphenyl)acetic acid tert-butyl ester, 7.32 g, (96%) as white solid. 1H NMR (CDCl3) δ: 7.931 (1H, s, br), 6.955 (1H, d, J=7.56 Hz), 6.799 (1H, s), 6.688 (1H, d, J=7.81 Hz), 3.551 (2H, S), 2.299 (3H, s), 1.472 (9H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])(=O)=O>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(CO)Oc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(Br)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2-(4-bromophenoxy)-2-methylpropan-1-ol (25.4 g) and 2,6-lutidine (30.2 mL) in dichloromethane (300 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (28.6 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (37.1 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:7][CH:8]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:16][C:15]1[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1csc(Nc2ncccc2OCc2ccccc2)n1)c1ccccc1
Reaction time: 2 h
Yield: 21.8 %

Procedure:
Crude 4-(2-aminoethyl)-N-(3-(benzyloxy)pyridin-2-yl)thiazol-2-amine (Example 134, Step A; 0.25 g, 0.766 mmol) was dissolved in DMF (10 mL), and triethylamine (0.427 ml, 3.06 mmol) was added, followed by benzoyl chloride (0.215 g, 1.53 mmol). The reaction mixture was stirred 2 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 2:3 hexane:ethyl acetate to provide the title compound (0.072 g, 21.8% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.85 (t, 2H), 3.58 (m, 2H), 5.26 (s, 2H), 6.69 (s, 1H), 6.89 (m, 1H), 7.32-7.59 (m, 9H), 7.82-7.87 (m, 3H), 8.55 (t, 1H), 9.95 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
22.4 g (160 mmol) of 4-fluoro-benzeneboronic acid, 34 g (153.5 mmol) of 2,5-dibromopyridine and 1.24 g of tetrakis(triphenylphosphine)palladium were dissolved in 240 ml of ethanol and 480 ml of toluene. 480 ml of a 2 N sodium carbonate solution were added and the resulting mixture was heated to 50° C. with stirring for 2 h. After addition of 400 ml of ethyl acetate the mixture was filtered, the phases were separated and the organic phase was washed with a saturated sodium chloride solution, dried and evaporated. The obtained product was purified by column chromatography (silica gel, dichloromethane/heptane 1:1) and preparative HPLC (RP 18). Yield: 12 g.
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CC=C.C[N+]1([O-])CC[O:24]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:36][C:37]([CH3:39])=[O:38]>O>[OH:38][CH:37]([CH2:39][OH:24])[CH2:36][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19]
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCCCCCCCn1c(=O)c(C)cn(C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cn(C)c(=O)n(CCCCCCCC(O)CO)c1=O
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 3-(8-nonenyl)-1-methylthymine (2.63 g, 9.9 mmol), prepared above, 4-methylmorpholine-N oxide (1.39 g, 12 mmol), and potassium osmate (IV) dihydrate (7 mg, 2×10-5 mol) in acetone (20 ml) and water (10 ml) was stirred for 18 hours. After addition of a saturated aqueous solution of sodium hydrosulfite (10 ml) and 15 minutes of stirring, the reaction mixture was extracted with dichloromethane (50 ml) and with two 50 ml aliquots of dichloromethane/20% methanol. The combined organic layers were washed with water (15 ml) and saturated aqueous salt solution (15 ml), and then dried over sodium sulfate. The solvent was evaporated under vacuum, leaving a white solid residue. Recrystallization of the solid in ethanol yielded 2.68 g of 3-(8,9-dihydroxynonyl)-1-methylthymine (91% yield).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn]([C:48]#[N:49])(CCCC)CCCC)CCC.Cl[C:51]1[CH:52]=[CH:53][CH:54]=[C:55]2[C:60]=1[N:59]=[C:58]([C:61]1[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=1)[C:57]([CH3:68])=[C:56]2[NH:69][C:70]1[C:71]([C:82]2[CH:83]=[N:84][CH:85]=[C:86]([O:88][CH3:89])[CH:87]=2)=[N:72][CH:73]=[C:74]([N:76]2[CH2:81][CH2:80][O:79][CH2:78][CH2:77]2)[CH:75]=1>CN1CCCC1=O.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]>[CH3:89][O:88][C:86]1[CH:87]=[C:82]([C:71]2[C:70]([NH:69][C:56]3[C:55]4[C:60](=[C:51]([C:48]#[N:49])[CH:52]=[CH:53][CH:54]=4)[N:59]=[C:58]([C:61]4[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=4)[C:57]=3[CH3:68])=[CH:75][C:74]([N:76]3[CH2:77][CH2:78][O:79][CH2:80][CH2:81]3)=[CH:73][N:72]=2)[CH:83]=[N:84][CH:85]=1
Reactant: COc1cncc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3c(Cl)cccc23)c1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: COc1cncc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3c(C#N)cccc23)c1
Temperature: 100 °C
Reaction time: 21.5 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.9 mg, 4.05 μmol), tri-n-butyltin cyanide (8.00 mg, 0.025 mmol), 8-chloro-N-(5′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine (0.014 g, 0.025 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added Pd2dba3 (0.927 mg, 1.01 μmol). The reaction mixture was heated to 100° C. and stirred for 21.5 h. The crude product was filtered through a plug of alumina eluting with EtOAc. The filtrate was cond in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes) to give the desired product. The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 4-(5′-methoxy-5-morpholino-2,3′-bipyridin-3-ylamino)-3-methyl-2-(4-methylpyridin-2-yl)quinoline-8-carbonitrile. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.53 (1H, d, J=5.1 Hz), 8.42 (1H, d, J=1.8 Hz), 8.30 (1H, d, J=2.7 Hz), 8.06-8.15 (2H, m), 7.97 (1H, s), 7.84 (1H, m), 7.56 (1H, dd, J=8.4, 7.2 Hz), 7.39 (1H, dd, J=2.8, 1.9 Hz), 7.24 (1H, m), 6.30 (1H, br. s.), 5.47 (1H, s), 3.90 (3H, s), 3.64 (4H, t, J=4.9 Hz), 3.25 (4H, br. s.), 2.50 (3H, s), 2.43 (3H, s). Mass Spectrum (ESI) m/e=544.2 (M+1).