Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:12]=[N:11][C:10]1=2.CCOCC>CO>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7])=[O:21])[CH:12]=[N:11][C:10]1=2
Reactant: NCCNCCO
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CO
Solvent: CCOCC
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCNCCO
Reaction time: 1 h
Yield: 38 %

Procedure:
0.500 (4,80 mmol) 2-(2-aminoethylamino)ethanol and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated at 120° C. with stirring in a 10 ml round bottom flask for one hour. The reaction mixture was chromatographed on a 15 g silica-gel column using an eluant of 60% methanol/40% ethyl acetate. After 200 ml of solvent had passed through column, the eluant was changed to 80% methanol/20% ethyl acetate and finally to 100% methanol. The fractions containing the product were combined and evaporated to yield a colorless oil. The oil was treated with 50 ml ether and 5 ml methanol and was agitated with a spatula. The oil was allowed to stand overnight and the resulting white solid was obtained by filtration (120 mg). The solid was washed with ether and was found to be somewhat hygroscopic. Yield: 38%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9]2=[O:16].C(=O)([O-])[O-].[K+].[K+].CCC(=O)CC.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>O>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:10]1[C:9](=[O:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([O:5][C:4]3[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=3)[CH:7]=2)[C:11]1=[O:15]
Reactant: COC(=O)CBr
Reactant: O=C1NC(=O)c2cc(Oc3ccc(F)c(F)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(=O)CC
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)c(F)c3)cc2C1=O
Temperature: 105 °C

Procedure:
To a pressure tube was added 5-(3,4-difluoro-phenoxy)-isoindole-1,3-dione (680 mg), potassium carbonate (1 g), 3-pentanone (20 ml), and methyl bromoacetate (295 μL). The resulting mixture was heated to 105° C. for 17 h. The reaction was diluted with 20 ml water and extracted with ethyl acetate (2×). The organic layer was dried and concentrated. The mixture was purified through silica gel chromatography with 4:1 hexanes/ethyl acetate and 3:1 hexanes/ethyl acetate to give 657 mg title compound. 1H NMR (200 MHz, DMSO) δ 7.95 (d, J=9.0 Hz, 1H), 7.64-7.41 (m, 4H), 7.15-7.08 (m, 1H), 4.44 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Si]([N:11]=[C:12]=[O:13])(C)C>C(O)(C)C>[N:1]1([C:12]([NH2:11])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)N1CCOCC1
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a stirred solution of morpholine (1.3 mL, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution stirred overnight before the volatiles were removed in vacuo to give morpholine-4-carboxylic acid amide (2.0 g, quant.) as a solid; 1H-NMR (300 MHz, d6-DMSO) 6.00 (2H, s), 3.51-3.54 (4H, s), 3.23-3.26 (4H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:5][CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C=O)CC1
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (Bioorg. Med. Chem. Lett., 2008, 18(6), 2188) (135 mg, 0.72 mmoles) in DCM (8 mL) was added Dess-Martin periodinane (277 mg, 0.65 mmole). After stirring 1 hr, the reaction was filtered through celite and concentrated to a yellow oil which was further purified by Isolera (7%-70% ethyl acetate/hexanes) to provide 84 mg (87%) of tert-butyl (1-formylcyclopropyl)-carbamate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:28]([O:30]C)=[O:29])=[CH:24][CH:25]=3)[C:20]2=[O:32])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.O.O[Li].O>CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH:19]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)[C:20]2=[O:32])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)C(CCC1CCN(C(=O)OCc3ccccc3)CC1)C2
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C(=O)C(CCC1CCN(C(=O)OCc3ccccc3)CC1)C2

Procedure:
A solution of 1-3 (0.6 g, 1.6 mmol) in 1:1:1 THF/CH3OH/H2O (12 mL) was treated with LiOH·H2O (0.34 g, 8 mmol) at room temperature for 2 h. The solution was diluted with EtOAc and extracted with saturated NaHCO3 solution. The basic aqueous layer was acidified to pH 3-4 with 10% KHSO4 solution and extracted with EtOAc. The organic layers were dried (MgSO4), filtered, and evaporated to give 1-4 as a brown oil. Rf (9:0.5:0.5 CH2Cl2 /CH3OH/HOAc) 0.36 1H NMR (300 MHz, CD3OD) δ 8.28 (m, 2H), 7.7 (d, 1H), 7.3 (m, 5H), 5.1 (s, 2H), 4.12 (d, 2H), 3.45 (m, 1H), 2.9 (dd, 1H), 2.8 (m, 2H), 2.4 (dd, 1H), 1.7 (bd, 2H), 1.6-1.0 (m, 7H).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][O:48][C:49]1[CH:50]=[CH:51][C:52]2[NH:58][C:57](=[O:59])[N:56]([CH:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)[CH2:55][CH2:54][C:53]=2[CH:66]=1.Br[C:68]1[CH:69]=[C:70]([C:74]([N:76]2[C:84]3[C:79](=[CH:80][C:81]([F:85])=[CH:82][CH:83]=3)[CH2:78][CH2:77]2)=[O:75])[CH:71]=[CH:72][CH:73]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:85][C:81]1[CH:80]=[C:79]2[C:84](=[CH:83][CH:82]=1)[N:76]([C:74]([C:70]1[CH:69]=[C:68]([N:63]3[CH2:64][CH2:65][CH:60]([N:56]4[CH2:55][CH2:54][C:53]5[CH:66]=[C:49]([O:48][CH3:47])[CH:50]=[CH:51][C:52]=5[NH:58][C:57]4=[O:59])[CH2:61][CH2:62]3)[CH:73]=[CH:72][CH:71]=1)=[O:75])[CH2:77][CH2:78]2
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cccc(Br)c1)N1CCc2cc(F)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cccc(C(=O)N4CCc5cc(F)ccc54)c3)CC1)C(=O)N2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 7 mg (31 μmol) palladium(II) acetate and 20 mg (32 μmol) BINAP were added to 86 mg (0.31 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.31 mmol) (3-bromo-phenyl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.16 g (0.48 mmol) caesium carbonate in 4.0 mL dioxane, and the mixture was stirred overnight at 120° C. The reaction mixture was then evaporated down and the residue was dissolved in DMF/MeOH and purified by preparative HPLC-MS.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][S:6]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)(=[O:8])=[O:7].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][NH:5][S:6]([CH:9]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=5[O:13][CH2:12][CH2:11][CH2:10]4)(=[O:8])=[O:7])[CH2:38][CH2:39]3)=[CH:30][CH:29]=2)=[CH:25][CH:26]=1
Reactant: O=S(=O)(NCCCCl)C1CCCOc2ccccc21
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: O=S(=O)(NCCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)C1CCCOc2ccccc21

Procedure:
The compound (10) synthesized in Reference Example 10 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([N+:20]([O-])=O)=[C:4]([NH:23][C:24](=[O:26])[CH3:25])[CH:3]=1>CO.C(Cl)Cl.[Pd]>[NH2:20][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[NH:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(6-chloro-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamide (220 mg, 0.593 mmol) in methanol (5 mL) and CH2Cl2(5 mL) was added 10% catalytical amount Pd/C. The reaction mixture was stirred at room temperature under 1 atm of H2 for 1 h, then filtered. The filtrate was concentrated to afford the title compound, which was used for the next step without further purification. MS (m/z): 342 (M+1)+.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[OH:25][C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/[C:32](O)=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:32](=[O:33])/[CH:31]=[CH:30]/[C:29]1[CH:35]=[CH:36][C:26]([OH:25])=[CH:27][CH:28]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)/C=C/c2ccc(O)cc2)C(=O)O)cc1
Yield: 45 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine was reacted with trans-4-hydroxycinnamic acid under the conditions described in example 86 to yield 45% of the desired product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12]CC(C1C=CC(Br)=CC=1)=O>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2].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>[CH3:12][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(C#N)cc1
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]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(C#N)cc1
Yield: 89 %

Procedure:
As described for the preparation of 4-cyanoacetophenone (Synth. Commun 1994, 887-890), a mixture of 4-bromopropiophenone (5.65 g, 26.4 mmol), Zn(CN)2 (1.80 g, 15.3 mmol), and Pd(PPh3)4 (2.95 g, 2.6 mmol) was refluxed at 80° C. in deoxygenated DMF (35 mL, stored over 4 Å molecular sieves, bubbled with Ar before use) for 18 h. The mixture was partitioned between toluene (100 mL) and 2N NH4OH (100 mL). The organic phase was extracted with 2N NH4OH (100 mL), washed with saturated aqueous NaCl (2×100 mL), dried, and concentrated in vacuo. A 10 mmol scale reaction was done similarly and the crude products were combined. Flash chromatography (330 g silica, 6/1 petroleum ether—EtOAc) afforded the desired compound as a white solid (5.17 g, 89%).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[CH3:8][S:9]([CH2:12][C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].Cl.[OH-].[Na+]>O1CCCC1.O.CO.C(O)=O>[CH3:8][S:9]([CH2:12][C:13]1[CH:14]=[C:15]([NH:19][CH3:1])[CH:16]=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=CO
Product: CNc1cccc(CS(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[3-(Methylsulfonylmethyl)phenyl]N-methylamine may be obtained by carrying out the procedure in the following manner: a mixture of 9.65 cm3 of formic acid and 19.63 cm3 of acetic anhydride is heated at 50° C. for 3 hours under argon, and then the solution obtained is allowed to return to room temperature. 40 cm3 of tetrahydrofuran are poured in and the medium is cooled to −20° C. After stirring for 2 hours at −20° C., a solution of 14.8 g of 3-(methylsulfonylmethyl)phenylamine is poured in while the temperature is maintained. After stirring for 2 hours at −20° C., and then for 48 hours at 20° C., the mixture is filtered, the solid is drained and then washed with three times 50 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa). A solid A is obtained. The filtrate is concentrated to half the volume, the resulting suspension is filtered, the solid is drained, washed with diisopropyl ether and dried. A solid B is obtained. The two solids A and B are combined and taken up in 375 cm3 of tetrahydrofuran and the mixture, cooled to 0° C., is supplemented, over 20 minutes, with 80 cm3 of a 2 M solution of borane-dimethyl sulfide complex in tetrahydrofuran and then heated at reflux temperature for 3 hours. The reaction mixture, cooled to +5° C., is supplemented over 20 minutes with 60 cm3 of methanol, stirred for 1 hour at room temperature and then supplemented with gaseous hydrochloric acid to a pH of 1. The mixture is heated under reflux for one hour and then supplemented with 300 cm3 of water and with a 3 N solution of sodium hydroxide to pH 8. The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution, and with brine, and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of 4 N sulfuric acid, the solution obtained is washed with 100 cm3 of ethyl acetate, then alkalinized to pH 8 with 3 N sodium hydroxide and with a saturated aqueous sodium carbonate solution and is then extracted with twice 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of N-[3-(methylsulfonylmethyl)phenyl]N-methylamine are obtained in the form of a pink solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]3[CH2:16][CH2:15]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@@H:12]([CH:14]3[CH2:15][CH2:16]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCCCCC
Solvent: CCO
Product: C[C@H](C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 48.1 %

Procedure:
Racemic 3-amino-7-bromo-5-(1-cyclopropylethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 164 (1.12 g) was resolved by HPLC (column: CHIRALPAD AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=800/200(v/v)) to give the title compound (539 mg) having a longer retention time.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[OH-:16].[Na+].Cl>CO>[O:9]([CH2:8][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc(COc2ccccc2)ccn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1cc(COc2ccccc2)cc[nH]1
Temperature: 170 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-(phenoxymethyl)pyridine (2.34 g, 10.68 mmol) in anhydrous methanol (30 mL) in a steel bomb was added sodium hydroxide (3.20 g, 80.11 mmol). The reaction mixture was stirred at 170° C. for 16 hours, cooled to 0° C. and neutralized with cold concentrated hydrochloric acid, followed by the addition of methanol (10 mL) and filtration. The filtrate was concentrated in vacuo and the residue was washed with methanol and hexane. The title compound was obtained as a colorless solid in 93% (2 g): 1H NMR (300 MHz, CDCl3) δ 13.00 (br s, 1H), 7.35-7.25 (m, 3H), 6.99-6.90 (m, 3H), 6.64 (s, 1H), 6.34 (d, J=6.6 Hz, 1H), 4.93 (s, 2H); MS (ES+) m/z 202.2 (M+1).
Reaction SMILES: [F:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:4]([C:3]2[C:2]([F:1])=[N:9][CH:8]=[CH:7][C:6]=2[I:10])[OH:5])=[CH:14][CH:13]=1
Reactant: O=Cc1c(I)ccnc1F
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1c(I)ccnc1F
Reaction time: 0.25 h

Procedure:
To a solution of 2-fluoro-4-iodonicotinaldehyde (1.50 g, 5.98 mmol) in anhydrous THF (20 mL) at −78° C. was slowly added a solution of (4-chlorophenyl)magnesium bromide (1 M in Et2O) (6.57 mL, 6.57 mmol). After 15 minutes at −78° C., the reaction was quenched with MeOH followed by saturated aqueous ammonium chloride, and the product was extracted with CH2Cl2 (4×). The organic layers were combined, dried over a cotton plug and concentrated to dryness under vacuum. The residue was used without any purification in the next step. LC/MS m/z 364 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:11]1[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][N:12]=1.[I-].[CH3:26][N+:27]([CH3:29])=[CH2:28]>CN(C)C=O>[CH3:26][N:27]([CH2:29][C:5]1[S:1][C:2]([CH2:6][S:7][CH2:8][CH2:9][NH:10][C:11]2[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][N:12]=2)=[CH:3][CH:4]=1)[CH3:28]
Reactant: O=c1[nH]c(NCCSCc2cccs2)ncc1Cc1cccnc1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)s1

Procedure:
2-[2-(2-Thienylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone is reacted with an excess of dimethyl(methylene)ammonium iodide in dimethylformamide at room temperature to give 2-[2-(5-dimethylaminomethyl-2-thienylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:71]([NH2:75])([CH3:74])([CH3:73])[CH3:72]>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:75][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:39]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)(C)C)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and t-butylamine (8.71 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14.8 mg, 46%). LC-MS m/z 595 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH2:11]([OH:15])[C:12](=[CH2:14])[CH3:13].[OH-].[K+]>CS(C)=O>[F:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:15][CH2:11][C:12]([CH3:14])=[CH2:13])[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1c(F)cccc1F
Reactant: C=C(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=C(C)COc1cccc(F)c1C#N
Temperature: 0 °C
Yield: 88 %

Procedure:
In a flask were placed 250.0 g (1.80 moles) of 2,6-difluorobenzonitrile, 129.8 g of (1.80 moles) of methallyl alcohol, and 1500 mL of dimethyl sulfoxide. This mixture was stirred vigorously while 124.76 g (1.89 moles) of 85% powdered potassium hydroxide was added in portions. This addition required 2 hours during which the temperature was maintained below 45° C. The reaction mixture was stirred at ambient temperature for approximately 21 hours. At the conclusion of this period the mixture was poured into 4 L of an ice/water mixture. This mixture was divided into two equal portions, and each was extracted twice with 1 L of ethyl acetate. The extracts were combined and washed twice with a saturated aqueous solution of sodium chloride. The extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving 302.7 g of 6-fluoro-2-(2-methyl-2-propen-1-yloxy)benzonitrile as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][Si:10]([CH3:26])(N(CC)CC)[CH2:11][CH2:12][Si:13]([CH3:20])([CH3:19])N(CC)CC>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[Si:13]([CH3:20])([CH3:19])[CH2:12][CH2:11][Si:10]2([CH3:26])[CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCN(CC)[Si](C)(C)CC[Si](C)(C)N(CC)CC
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(Br)c1

Procedure:
The alpha,omega-aniline terminated dimethyl siloxanes are prepared, starting with 3-bromoaniline, in which the amine functionality is protected, such as by reaction with 1,1,4,4-tetramethyl-1,4-bis(N,N-diethylamino)-1,4-disilabutane, to form 1-(3-bromophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane. The protected bromoaniline is then reacted with an alkyllithium or with magnesium to form the corresponding lithio or Grignard compound, respectively, which is then reacted with chlorodialkylsilane to form 1-(3-(dialkylsilyl)phenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane. This reaction places the silane functionality in the meta position. Next, the protected dimethylsilane aniline is subjected to deprotection to form 3-aminophenyldialkyl silane, which is considered to be novel. This silane is then hydrolyzed to form the corresponding silanol, also considered to be novel. The silanol is then condensed to form bis(3-aminophenyl)-1,1,3,3-tetraalkyldisiloxane.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:25]=[C:26]([NH:39][C:40]([NH:42][CH2:43][CH2:44][OH:45])=[O:41])[CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>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].O.CCO.COCCOC>[F:23][C:24]1[CH:25]=[C:26]([NH:39][C:40]([NH:42][CH2:43][CH2:44][OH:45])=[O:41])[CH:27]=[CH:28][C:29]=1[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 21.7 %

Procedure:
A solution of (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) (100 mg, 0.31 mmol), 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 32) (149 mg, 0.46 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (15 mg, 0.018 mmol) and sodium carbonate (49 mg, 0.46 mmol) in 2 ml of a 7:3:2 mixture of DME:EtOH:H2O respectively was heated in the microwave at 130° C. for 1 hour. The reaction was concentrated in vacuo and the residue redissolved in a mix of MeOH/DCM. It was loaded onto an SCX cartridge and washed with two column volumes of MeOH/DCM before being eluted with 2M NH3 in MeOH and concentrated in vacuo. The sample was then purified via preparative HPLC at high pH to yield the title compound (32.8 mg, 22%).