Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[N:14]([N:15]=1)[C:13]1[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=1[O:11][CH2:10][CH2:9]2)=O)C.[NH3:21].CO>>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[N:14]([N:15]=[C:6]([C:4]([NH2:21])=[O:3])[CH:7]=3)[C:13]=2[CH:16]=1
Reactant: N
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Solvent: CO
Product: NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Yield: 80 %

Procedure:
9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid ethyl ester (1.51 g, 4.48 mmol) in 2M ammonia/methanol solution (70 mL) was heated in a pressure bomb at approximately 120° C. (external temperature) for 30 h, then allowed to cool. The mixture was filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 100% ethyl acetate in cyclohexane) to give 9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid amide as a pale yellow solid (1.11 g, 80%). LCMS: RT=4.00 min, M+H+=308/310, [M+Na]+=330/332.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>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:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]4[C:23]([F:22])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
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+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (302.9 mg, 0.661 mmol), 2-fluoro-3-pyridineboronic acid (102 mg, 0.727 mmol), potassium carbonate (457 mg, 3.31 mmol), and tetrakis(triphenylphosphine)palladium(0) (38.2 mg, 0.033 mmol). The vial was flushed with Ar (g), then dioxane (3306 μL) and water (1.7 mL) were added in sequence. The vial was sealed and placed in a 75° C. oil bath for 2 hours. The mixture was diluted with EtOAc (15 mL) and brine (15 mL). The layers were separated, and the aq. layer was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH2:11])[C:4]([NH2:10])=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=O)=O)=[CH:15][CH:14]=1>O1CCOCC1.O>[ClH:1].[ClH:1].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[N:10][C:4]3[C:3](=[CH:8][CH:7]=[C:6]([NH2:9])[CH:5]=3)[N:11]=2)=[CH:17][CH:18]=1
Reactant: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Nc1ccc(N)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc2c1
Yield: 167.3 %

Procedure:
98.04 mg (0.5 mmol) of 1,2,4-benzenetriamine dihydrochloride and 121.2 mg (0.5 mmol) of 4,4′-dihydroxybenzil were dissolved in 2 ml of 1:1 mixture of dioxane-water. The reaction was refluxed for 3 hours. Then solvent was removed in vacuo. The residue was dissolved in 2 ml of methanol and this solution was added dropwise to 40 ml of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacuo to give 168.3 mg (83.7% yield) of the product. 98.7% purity by LC/MS (230 DAD). Mass-spec [ES+]=330.8. 1H NMR (500 MHz, MeOH-d4) 6.76–6.77 (2H, d), 6.87–6.89 (2H, d), 7.05–7.06 (1H, d), 7.29–7.31 (2H, d), 7.38–7.40 (2H, d), 7.50–7.52 (1H, m), 7.99–8.01 (1H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[C:24]([F:27])([F:26])[F:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]([O:35]CC)=[CH2:34])CCC>O1CCOCC1.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>[CH2:17]([O:16][C:11]1[C:10]([C:24]([F:27])([F:26])[F:25])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1[C:33](=[O:35])[CH3:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccc(Br)c1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (2.93 g, 2.54 mmol) to a solution of 1,3-bis-benzyloxy-4-bromo-2-trifluoromethyl-benzene (11.10 g, 25.4 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (10.08 g, 27.92 mmol) in dioxane (250 mL) and stir. Purge reaction vessel with argon. Heat to 100° C. After 6 hours, cool to ambient temperature and concentrate under reduced pressure. Add 2N aqueous hydrochloric acid (50 mL), and tetrahydrofuran (200 mL) and stir. After 30 minutes add water and extract with ethyl acetate. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield a residue. Purify the residue by flash chromatography eluting with a gradient of 0-20% ethyl acetate:hexanes to yield the title compound as a clear oil (6.10 g, 60%): 1H NMR (CD3CN) δ 2.48 (s, 3H), 4.89 (s, 2H), 5.25 (s, 2H), 7.08 (d, 1H), 7.33-7.48 (m, 10H), 7.83 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([CH3:12])[CH2:7][CH:6]1[CH3:13])=[O:4].[S-:14][C:15]#[N:16].[K+].[I-].[Na+].C(O)C>C1C=CC=CC=1>[S:14]([CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([CH3:12])[CH2:7][CH:6]1[CH3:13])=[O:4])[C:15]#[N:16]
Reactant: CC1CC(C)N(C(=O)CCl)C(C)C1
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CC1CC(C)N(C(=O)CSC#N)C(C)C1

Procedure:
1-(α-Chloroacetyl)-2,4,6-trimethylpiperidine (18 grams; 0.9 mol), potassium thiocyanate (18 grams; 0.2 mol), sodium iodide (a few crystals) and ethanol (100 ml) were charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux for a period of about 3 hours. After this time the mixture was cooled and filtered. The filtrate was evaporated leaving a solid product. The solid was then extracted with two 150 ml portions of hot benzene. The extracts were combined and evaporated under reduced pressure to yield an oil. This oil was refined by chromatography using Fuller's earth as an adsorbent and benzene as the elluent. The first 1000 ml of eluent were collected from the column and were stripped of benzene to yield 1-(α-thiocyanoacetyl)-2,4,6-trimethylpiperidine as a yellow oil having a refractive index of 1.5183 at 25° C. and having the following elemental analysis as calculated for C11H18N2OS.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:19][O:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)(=[O:11])=[O:10])[CH2:17][CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (138 mg, 0.72 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (195 mg, 0.60 mmol), 1-hydroxybenzotriazole (97.0 mg, 0.72 mmol), 4-fluorobenzoic acid (84.0 mg, 0.60 mmol) and N,N-diisopropylethylamine (233 mg, 1.80 mmol) in N,N-dimethylformamide (8 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (50 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 50/50) to give 4-fluoro-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)benzamide (217 mg, 81%) as a white solid: LCMS: 447 [M+1]+. 1H NMR (DMSO-d6) δ: 1.71 (m, 2H), 1.88 (m, 2H), 3.07 (m, 4H), 3.97 (t, 1H), 7.27 (t, 2H), 7.74 (m, 2H), 7.98 (m, 2H), 8.10 (m, 2H), 11.4 (s, 1H).
Reaction SMILES: [Na].C(O)C.[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][C:18]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:18]1[CH:19]=[C:20]([C:21](=[O:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:29]=[CH:30][C:17]=1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])([O-:33])=[O:32]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole) of sodium metal with 200 ml. of ethanol, at 0° C. was added 32 g. (0.2 mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of 4-chloro-3-nitrobenzophenone. The mixture was allowed to stir at room temperature for 2 hours and was then poured into 400 ml. of ice cold 2N hydrochloric acid and 300 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to an oil. The residual oil was induced to crystallize by trituration with hexane containing trace amounts of diisopropyl ether, 34.75 g., m.p. 68°-70° C. The sample was further purified by trituration with hot hexanediisopropyl ether, 30.84 g. (80% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:34]1[CH:39]=[C:38]([CH:40]=[O:41])[C:37]([CH:42]=O)=[CH:36][CH:35]=1.O>C(O)(=O)C>[CH:29]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:1]3[CH2:42][C:37]4[C:38](=[CH:39][CH:34]=[CH:35][CH:36]=4)[C:40]3=[O:41])=[CH:4][CH:5]=2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN)cc1)C1CCCC1
Reactant: O=Cc1ccccc1C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Reaction time: 1 h

Procedure:
At RT, 50 mg (0.11 mmol) of (+/−)-tert-butyl 3-[3-({[4-(aminomethyl)phenyl](cyclopentyl)acetyl}amino)-2-methylphenyl]propanoate and 16.4 mg (0.12 mmol) of phthaldialdehyde were dissolved in 2.5 ml of glacial acetic acid, and the mixture was left to stand for 1 h. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative RP-HPLC. This gave 53 mg (85% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[C:19]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[C:19]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:22])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ncccn4)CC3C2)n1
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (1.4 g, 6.5 mmol), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (1.4 g, 6.5 mmol), and TEA (1.3 mL, 9.7 mmol) in DMF (32.0 mL) was added HATU (2.7 g, 7.1 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (1×). The combined organic phases were dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using silica gel chromatography (0-5% MeOH in EtOAc) to yield pure title compound (1.2 g, 44%). MS (ESI) mass calcd. For C23H23FN6O, 418.48; m/z found 419.2 [M+H]+. 1H NMR (CDCl3): 8.91-8.56 (m, 2H), 7.47-7.42 (m, 1H), 7.24-7.14 (m, 3H), 6.30 (s, 1H), 3.81 (dd, J=11.6, 7.2 Hz, 1H), 3.72 (ddd, J=9.0, 7.2, 2.2 Hz, 2H), 3.68-3.47 (m, 4H), 3.31 (dd, J=11.0, 4.8 Hz, 1H), 3.05-2.89 (m, 2H), 2.31 (s, 6H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C:8]1=[O:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:31]([C:33]1[CH:46]=[CH:45][C:36]([CH2:37][N:38]2[C:42]([CH:43]=O)=[CH:41][N:40]=[CH:39]2)=[CH:35][C:34]=1[F:47])#[N:32].CCOC(C)=O>ClCCCl>[C:31]([C:33]1[CH:46]=[CH:45][C:36]([CH2:37][N:38]2[C:42]([CH2:43][N:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([OH:2])[CH:4]=4)[C:8](=[O:13])[CH2:9]3)=[CH:41][N:40]=[CH:39]2)=[CH:35][C:34]=1[F:47])#[N:32]
Reactant: O=C1CNCCN1Cc1cccc(O)c1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1ccc(Cn2cncc2CN2CCN(Cc3cccc(O)c3)C(=O)C2)cc1F
Reaction time: 16 h

Procedure:
To a solution of the amine hydrochloride from Step K (theoretically 0.22 mmol) in 2 mL of 1,2-dichloroethane was added 4 Å powdered molecular sieves (100 mg), followed by sodium triacetoxyborohydride (70 mg, 0.33 mmol). The aldehyde from Step G (51 mg, 0.22 mmol) was added, and the reaction was stirred for 16 hours. The reaction was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:3]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:18][C:16]([CH3:19])([CH3:17])[CH2:15][O:14][C:4]1[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=[C:2]([NH2:1])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(O)COc1cc(N)nc(N2CCOCC2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(COc1cc(N)nc(N2CCOCC2)n1)O[Si](C)(C)C(C)(C)C
Reaction time: 72 h
Yield: 34.4 %

Procedure:
1-(6-amino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol (1.03 g; 3.8 mmol) and imidazole (500 mg; 8 mmol) were-dissolved in dimethyl formamide (16 mL). To this solution was added tert-butyldimethylsilyl chloride (1.2 g; 8 mmol), and it was stirred for 72 hours. The solution was poured into ethyl acetate (100 mL) which was then washed with water (3×200 mL). The organic layer was separated, dried over magnesium sulfate, and purified by column chromatography to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-2-methyl-propoxy]-2-morpholin-4-yl-pyrimidin-4-ylamine (500 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A mixture of 2,4-dichloronicotinic acid (5.0 g, 26 mmol), benzyl bromide (3.7 mL, 31 mmol) and K2CO3 (7.2 g, 52 mmol) in DMF (50 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate, evaporated and then purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-dichloronicotinate (7.0 g, 96%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4].[Cl:21][C:22]([Cl:28])([S:26]Cl)[CH:23]([Cl:25])[Cl:24].ClCCl>O>[C:3]([C:5]1[C:6](=[O:20])[N:7]([S:26][C:22]([Cl:28])([Cl:21])[CH:23]([Cl:25])[Cl:24])[C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Cl)C(Cl)Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 1.60 g (0.04 mol) of NaOH in 45 ml of water is added 9.64 g (0.04 mol) of 5-cyano-1-(2,6-dimethylphenyl)uracil, obtained as in Example 1. After dissolution, 50 ml of ice cold dichloromethane is added, followed by a solution of 9.36 g (0.04 mol) of 1,1,2,2-tetrachloroethanesulphenyl chloride (prepared by the method of U.S. Pat. No. 3,395,180) in 15 ml. of dichloromethane. The mixture is stirred for 30 min at 4°. The aqueous layer is separated and discarded. The dichloromethane solution is dried and stripped at aspirator pressure. The unreacted sulphenyl chloride is then removed by trituration with pentane/dichloromethane (4:1). The resultant crude product is purified by slurrying at 30° in 60 ml of ethanol-free chloroform, allowed to cool to RT and filtered. To the filtrate is added hexane to the cloud point, and the mixture is then filtered to yield 5-cyano-1-(2,6-dimethylphenyl)-3-(1,1,2,2-tetrachloroethanesulphenyl)uracil, m.p. 180°-183°.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[N:7]2.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>CN(C=O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[N:11][C:2]=3[CH3:1])[N:7]=2)[CH2:16][CH2:17]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1nccc2nc(NCCN3CCNCC3)ccc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nccc2nc(NCCN3CCN(Cc4ccccc4)CC3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 8 (56.74 mg, 0.136 mmol) in DMF (10 mL) was added benzaldehyde (21.65 mg, 0.204), MP-triacetoxyborohydride (2.70 mmol/g, 302 mg, 0.816 mmol), and acetic acid (24.5 mg, 0.408 mmol). It was stirred at room temperature overnight. The resin was removed by filtration. The solvent was removed and chromatography on silica gel afforded compound 9 (46.0 mg, 93.6). 1H NMR (CD3OD, 400 MHz) δ 8.19 (d, 1H, J=5.5 Hz), 8.09 (d, 1H, J=7.5 Hz), 7.20-7.35 (m, 6H), 6.81 (d, 1H, J=7.5 Hz), 3.62-3.71 (m, 2H), 3.55 (s, 2H), 2.75 (s, 3H), 2.45-2.70 (m, 10H). LCMS (EI) m/z 362 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]([CH3:8])N(N)[O:5][CH:6]=1.[H-].[Na+].CC1OC(C)=CC=1[S:17]([Cl:20])(=[O:19])=[O:18]>>[O:5]1[CH:6]=[CH:2][CH:3]=[C:8]1[S:17]([Cl:20])(=[O:19])=[O:18]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Reactant: CC1C(Br)=CON1N
Agent: [H-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccco1

Procedure:
Furan-2-sulfonyl chloride was prepared by the method of Example 1 with 4-bromo-3-methyl-2-aminoisoxazole (0.354 g, 2.0 mmol), NaH (60% oil dispersion) (200 g, 5.0 mmol) and 2,5-dimethylfuran 3-sulfonyl chloride (0.467 g, 2.4 mmol). Flash chromatography (5% CH3OH/CHCl3) and recrystallization from CHCl3 /hexane provided 0.21 4 g (32% yield) of light brown crystals (m.p. 85.5°-87° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:12])[C:8]=1[CH2:9][O:10][CH3:11])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[C:7]([Cl:12])[C:8]=1[CH2:9][O:10][CH3:11]
Reactant: CC(C)OC(=O)Cl
Reactant: COCc1c(Cl)cc(N)cc1Cl
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: COCc1c(Cl)cc(NC(=O)OC(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
3,5-Dichloro-4-methoxymethylaniline (2.06 g) and N,N-diethylaniline (1.49 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.24 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3,5-dichloro-4-methoxymethylphenyl)carbamate (Compound No. 1) (2.62 g) in a yield of 89.6% nD26.2 1.5283.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([CH3:25])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(C)c3)nc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(C)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 148-1 (80 mg, 0.21 mmol) and 2-methyl-4-(tributylstannyl)pyridine 148-2 (75 mg, 0.21 mmol) in DMF (1.5 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (30 mg, 0.18 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetamide 148 as off-white solid. MS m/z 445.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.57 (s, 1H), 8.49 (d, 1H), 8.40 (d, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 2H), 3.70 (s, 2H), 3.50 (b, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 2.49 (s, 3H), 2.28 (s, 3H), 1.97 (s, 3H).