Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[S:22].N>O1CCCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:21](=[S:22])[NH2:23])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: NC(=S)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2 mmol) (Example 9, step 3) in dry tetrahydrofuran (10 mL) was treated with 1,1′-thiocarbonyldiimidazole (0.5 g, 3 mmol) and stirred at RT for 4 h. The solvent was removed and the resulting residue was dissolved in ammonia (2.0 M solution in methanol, 15 mL, 30 mmol) and stirred the resulting solution in a pressure tube at RT for 1 h followed by heating at 55° C. for 5 h. The solvent was removed under vacuum and the residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carbothioamide as a white solid. MS (ESI, pos. ion) m/z: 337 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][C:9]#[N:10]>CO>[C:8]([CH2:9][NH:10][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])#[N:7]
Reactant: N#CCN
Reactant: C=C1CC(=O)O1
Solvent: CO
Product: CC(=O)CC(=O)NCC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
While stirring at -10° to 0° C, 92 g of freshly distilled diketene are added dropwise to a solution of 400 ml of methanol and 56 g of freshly distilled aminoacetonitrile. The mixture is allowed to warm to room temperature and stirring is continued for 2 hours at 35° C in a water bath. The solvent is distilled off by rotary evaporation and the solid residue is suspended in cold ether. Suction filtration yields the colourless, crystalline, pure acetoacetic N-cyanomethylamide with a melting point of 63°-65° C.
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1COCC1>[CH:1]1([C:7](=[S:19])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C1CCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)C1CCCCC1
Yield: 78.7 %

Procedure:
Cyclohexanecarboxamide (1 g, 7.86 mmol) and Lawesson's Reagent (2 g, 4.94 mmol) in THF (50 mL) was heated at 70° C. for 3 h. Silica was added and the volatiles were removed under reduced pressure. The residue was column chromatographed with EtOAc/DCM to afford cyclohexanecarbothioamide (0.557 g, 49% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (br. s., 1H), 6.91 (br. s., 1H), 2.56 (tt, J=11.8, 3.3 Hz, 1H), 1.90-2.02 (m, 2H), 1.78-1.90 (m, 2H), 1.71 (d, J=12.0 Hz, 1H), 1.51 (qd, J=12.3, 2.8 Hz, 2H), 1.16-1.40 (m, 3H), e/z (ES+): 144 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](/[C:15](/[CH3:22])=[CH:16]/[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:30](=[NH:35])(OCC)[CH3:31]>O>[C:30]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1/[CH:16]=[C:15](/[C:7]1[CH2:6][C@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([OH:14])=[O:13])\[CH3:22])(=[NH:35])[CH3:31]
Reactant: CCOC(C)=N
Reactant: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=N)N1CCC[C@H]1/C=C(\C)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-{(2S)-pyrrolidin-2-yl]-1-methylethenyl]-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (0.44 g) in water (30 ml) was adjusted to pH 8.5 with aqueous potassium carbonate at 0° C. and ethyl acetimidate hydrochloride (5.4 g) was added in portions while adjusting around pH 8.5 with addition of aqueous potassium carbonate. After stirring for 15 minutes at pH 8.5, the reaction mixture was washed with a mixture of ethyl acetate and tetrahydrofuran (9:1 V/V, 150 ml), and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (80 ml) eluting successively with water (200 ml) and 5% aqueous isopropyl alcohol (200 ml). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[(E)-2-{(2S) 1-acetimidoyl-pyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (241 mg).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[CH:7]1[C:12]([CH:13]=O)=[CH:11][C:10]2[O:15][CH2:16][O:17][C:9]=2[CH:8]=1>>[CH:4]1([C:2]([CH:1]=[CH:13][C:12]2[CH:7]=[CH:8][C:9]3[O:17][CH2:16][O:15][C:10]=3[CH:11]=2)=[O:3])[CH2:6][CH2:5]1
Reactant: CC(=O)C1CC1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: O=C(C=Cc1ccc2c(c1)OCO2)C1CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 8.4 g. of cyclopropyl methyl ketone and 15 g. of piperonal according to the procedure described above in Preparation A1,affording 21.5 g., m.p. 85°-87° C. when recrystallized from ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[N:1]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C1CCN(N2CCNCC2)CC1
Reaction time: 8 h
Yield: 225.5 %

Procedure:
The product of step 4 (1.9 g, 5.79 mmol), N-BOC-4-piperidone (5.73 g, 28.8 mmol), NaBH(OAc)3 (6.1 g, 28.8 mmol) and 2M AcOH (5.76 ml, 11.52 mmol) were combined in CH2Cl2 (150 ml) and the mixture was stirred overnight. After the solvent was removed, NaOH (3N) was added and extractive work up with EtOAc followed by silica gel chromatography afforded pure piperazino-piperidine (2.21 g, 75% yield, Rf=0.18, hexanes/EtOAc, 1:1) as a syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N:10]1[N:14]=[CH:13][CH:12]=[N:11]1
Reactant: Cc1ccc(-n2nccn2)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2nccn2)c(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a stirred solution of (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanol (100 mg, 0.53 mmol) in chloroform (3 mL), thionyl chloride (76 mg, 0.63 mmol) was added dropwise at 0° C. and stirred for 1 h. Then the mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated under reduced pressure. Saturated aqueous NaHCO3 solution (5 mL) was added and extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to yield the title compound (100 mg, 91%). [TLC Rf=0.59 (ethyl acetate/hexane 30:70)].
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[C@@H:13]([CH3:32])[CH2:12]1)=O)C1C=CC=CC=1.[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH2:43])[CH:37]=[C:38]([F:40])[CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH:43][C:27]2[N:26]=[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][NH:17][C@@H:14]4[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]4[CH3:32])[CH:20]=3)[CH:30]=[CH:29][N:28]=2)[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cc(F)cc(F)c1
Product: C[C@H]1CNCC[C@H]1NCc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 136 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G3. LC-MS showed the product had the expected M+H+ of 418 LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.70 (s, 1H) 8.39 (d, 2H) 7.97 (d, 1H)) 7.74 (d, 2H) 7.00 (d, 2H) 6.86 (d, 1H) 4.57 (s, 2H) 4.06 (m, 1H) 3.88 (m, 1H) 3.72 (m, 1H) 3.57 (m, 1H) 3.42 (d, 2H) 3.10 (t, 2H) 2.92 (m, 2H) 2.38 (m, 2H) 1.38 (d, 3H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[S:21]1[CH:25]=[N:24][N:23]=[C:22]1[SH:26]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:26][C:22]3[S:21][CH:25]=[N:24][N:23]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Sc1nncs1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2nncs2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1,3,4-thiadiazole-2-thiol. m/e+ 353 for C18H17N4S2 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.22 (d, J=10.2 Hz, 2H), 7.82 (dd, J=1.8, 6.3 Hz, 2H), 7.57 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 2H), 7.12 (dd, J=1.5, 9.0 Hz, 1H), 5.91 (s, 2H), 2.41 (s, 3H), 2.34 (s, 3H) ppm.
Reaction SMILES: [N:1]([CH2:4][C:5]([F:43])([F:42])[CH2:6][CH2:7][C@H:8]([N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]([F:43])([F:42])[CH2:6][CH2:7][C@H:8]([N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH2:9][O:10][Si:11]([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:12])[CH3:13]
Reactant: CCCCCN([C@@H](CCC(F)(F)CN=[N+]=[N-])CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN([C@@H](CCC(F)(F)CN)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a stirred solution of the material from Step 9 (60 mg, 0.09 mmol) in THF (1.7 mL) and water (86 μL) was added triphenylphosphine (50 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then additional water (86 μL) was added, the reaction mixture was heated at reflux for 5 hours. Upon cooling to room temperature, the reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 42 mg of the title compound. LCMS (M+Na)=637.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1ncc(C#CCNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (2.81 g, 12.9 mmol) in TEA (25 mL) was added tert-butyl prop-2-yn-1-ylcarbamate (2.58 g, 16.6 mmol). The solution was degassed with argon. To the reaction mixture were added bis(triphenylphosphine)palladium(II) chloride (0.18 g, 0.26 mmol) and copper(I) iodide (0.098 g, 0.52 mmol). The reaction mixture was allowed to stir at 70° C. for 2.5 h and was then concentrated and diluted with EtOAc (100 mL). The mixture was filtered over a pad of Celite® and the resulting filtrate was washed with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl [3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-yl]carbamate (2.98 g, 79%) as a yellow solid. LCMS (FA): Rt=1.81 min, m/z=292.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Br)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[CH2:27]([NH2:30])[C:28]#[CH:29].[I-].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:30][CH2:27][C:28]#[CH:29])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2
Reactant: C#CCN
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 19, 8 -nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-nitro-1-[[(2-propynyl)amino] methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 25 8 -Chloro-1-[[(cyclopropylmethyl)amino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:8][O:9][CH2:10][P:11]([O:16]CC)([O:13]CC)=[O:12])=[C:5]([Cl:7])[N:6]=1.C[Si](Br)(C)C>>[Cl:1][C:2]1[S:3][C:4]([CH2:8][O:9][CH2:10][P:11]([OH:13])([OH:16])=[O:12])=[C:5]([Cl:7])[N:6]=1
Reactant: CCOP(=O)(COCc1sc(Cl)nc1Cl)OCC
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)COCc1sc(Cl)nc1Cl

Procedure:
2,4-Dichloro-5-(diethylphosphonomethoxymethyl)thiazole was deesterified with TMSBr as described in Step D, Example 1, to provide the title compound (no. 14.01) as a solid. HPLC Rt=4.36 min; negative ion electrospray MS M-1 found: 276/278.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH3:17])=[N:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1.Cl[C:22]1C=C(NC(N)=N)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[N:11]=[C:10]([C:12]2[N:16]([CH3:22])[C:15]([CH3:17])=[N:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1
Reactant: N=C(N)Nc1cccc(Cl)c1
Reactant: Cc1ncc(-c2ccnc(Nc3cccc(Cl)c3)n2)[nH]1
Product: Cc1ncc(-c2ccnc(Nc3cccc(Cl)c3)n2)n1C
Yield: 29.3 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1,2-dimethylimidazole (Method 1; 111 mg, 0.58 mmol) and 3-chlorophenylguanidine (97 mg, 0.58 mmol) were treated as described in Example 1 to give the title compound 51 mg, (29%) as a solid. NMR: 2.40 (s, 3H), 3.97 (s, 3H), 6.98 (d, 1H), 7.15 (d, 1H), 7.30 (t, 1H), 7.58 (d, 1H), 7.67 (s, 1H), 7.97 (s, 1H), 8.40 (d, 1H), 9.68 (s, 1H); m/z: 300.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C(O)C.[OH-].[Pd+2].[OH-].[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(Oc2nccnc2C2=CCOCC2)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1
Yield: 59.7 %

Procedure:
A solution of 4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (1.09 g, 4.0 mmol) in ethanol (40 mL) was added palladium hydroxide, 20 wt. % Pd (dry basis) on carbon, wet, Degussa type E101 NEW (0.284 g, 0.405 mmol) and hydrogenated (double-walled balloon pressure) at room temperature for 4 h. The reaction mixture was filtered via a pad of Celite, and the filtrate was concentrated in vacuo and chromatographed via flash column chromatography (20% to 80% EtOAc/Hexanes) to give 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (0.648 g, 59% yield) as a white solid. [M+1]=272.0.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][CH2:11][CH:12]=[CH2:13].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[C:21]([Cl:27])[CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:10]([CH2:11][CH:12]=[CH2:13])[C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:21]([Cl:27])[CH:20]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: C=CCCC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccc(Br)cc1Cl)C(=O)OCC
Yield: 71.1 %

Procedure:
Add LDA (5.27 mL, 10.5 mmol, 2.0 M) into a solution of ethyl pent-4-enoate (0.9 g, 7.0 mmol), in THF (125 mL) at −78° C. and stir for 15 minutes. Add 4-bromo-2-chlorobenzyl bromide (3.3 g, 10.5 mmol) and warm reaction to room temperature. Quench with ammonium chloride solution, extract the reaction mixture with methylene chloride and wash the organic layer with brine. Dry over sodium sulfate, filter and concentrate. Purify the residue with silica gel column (hexanes) to afford the title compound (1.65 g, 73%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](C4C=CC=C(F)C=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30].ClC1N=CC(C2C=CC3N(C(I)=C(NC(=O)C)N=3)N=2)=CC=1NS(C)(=O)=O.[F:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][C:61]=1[C:69]([N:71]1[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1)=[O:70]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:63]4[CH:64]=[CH:65][C:60]([F:59])=[C:61]([C:69]([N:71]5[CH2:76][CH2:75][O:74][CH2:73][CH2:72]5)=[O:70])[CH:62]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:28][S:29]([CH3:32])(=[O:30])=[O:31]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1cccc(F)c1
Reactant: O=C(c1cc(B(O)O)ccc1F)N1CCOCC1
Agent: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1I
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1ccc(F)c(C(=O)N2CCOCC2)c1
Yield: 64 %

Procedure:
Following the procedure described for N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (TFA salt) (Example 22), N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (0.0650 g, 0.128 mmol) (Example 21) was reacted with 4-fluoro-3-(morpholine-4-carbonyl)phenylboronic acid (0.0390 g, 0.154 mmol, Combi-Blocks, San Diego, Calif.) at 90° C. for 3 h to afford the title compound as a yellow solid (0.058 g, 64%). MS (ESI, positive ion) m/z: 588 (M−TFA+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 3.20 (s, 3H), 3.32 (s, 2H), 3.51-3.58 (m, 2H), 3.67 (br s, 4H), 7.45 (t, J=9.1 Hz, 1H), 7.80 (d, J=4.9 Hz, 1H), 7.99 (d, J=9.6 Hz, 1H), 8.04-8.09 (m, 1H), 8.31 (d, J=9.4 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.93 (d, J=2.2 Hz, 1H), 9.93 (s, 1H), 10.28 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:10][CH:9]=1)[CH3:7])[C:3](N)=[O:4].[OH-:24].[Na+]>>[O:1]=[C:2]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:24])=[O:4]
Reactant: CC(C(=O)C(N)=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C(=O)C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
A mixture of 2-oxo-3-[4-(1-oxo-2-isoindolinyl)phenyl] butanamide (0.30 g) and 10% aqueous sodium hydroxide solution (10 ml) is refluxed for 1 hour. After cooling the reaction mixture is washed with chloroform. The aqueous layer is acidified with diluted hydrochloric acid. The acidified layer is extracted with chloroform and the chloroform layer is washed with water, dried (Na2SO4) and evaporated. The residue is recrystallized from ethyl acetate to give colorless scales (0.23 g, 76%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[N:8][CH:7]=1>>[OH:16][C:9]1[C:10]2[C:15](=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][CH:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ncnc2ccccc12
Product: O=S(=O)(Cl)c1cccc2c(O)ncnc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 581.7 %

Procedure:
Chlorosulfonic acid (4.10 mL, 62.6 mmol) was slowly added to quinazolin-4-ol (1.09 g, 0.26 mmol). The resulting mixture was heated to 140° C. and stirred for 3 hours at the same temperature. After cooling to room temperature, the reaction mixture was poured into crushed ice. The mixture was extracted with DCM (100 mL×3), the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified via flash chromatography (5% PE: Ethyl Acetate) to give 370 mg of 4-hydroxyquinazoline-8-sulfonyl chloride. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (t, J=7.79 Hz, 1H) 8.26 (ddd, J=9.67, 7.92, 1.48 Hz, 2H) 9.02 (s, 1H). LC-MS: m/z 245.7 (M+H)+
Reaction SMILES: [SiH:1]([OH:4])([OH:3])[OH:2].Cl[SiH3].C[Si](C)(C)C1([Si](O)(O)O)C=CC=C1.C[Si](C)(C)C1([Si](Cl)(Cl)Cl)C=CC=C1.N[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)C>[C:34]1([Si:1]([OH:4])([OH:3])[OH:2])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O[SiH](O)O
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)C1([Si](Cl)(Cl)Cl)C=CC=C1
Agent: C[Si](C)(C)C1([Si](O)(O)O)C=CC=C1
Agent: [SiH3]Cl
Solvent: CCOCC
Product: O[Si](O)(O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
In general, silanetriol is synthesized by hydrolyzing chlorosilane or alkoxysilane. As a typical example of using chlorosilane, Jutzi et al. reported synthesis of (1-trimethylsilylcyclopenta-2,-4-dienyl)silanetriol with a yield of 98% by dissolving (1-trimethylsilylcyclopenta-2,-4-dienyl)trichlorosilane, a chlorosilane with large steric hindrance, in ethyl ether, slowly adding an aniline aqueous solution and stirring at 0° C. for 3 hours, removing the resulting aniline salt through filtration and then removing ethyl ether under reduced pressure [Organometallics 1997, 16, 5377]. However, this method involves a complicated process of removing a large amount of salts and is limited in that it is applicable only to silanes having substituents with large steric hindrance. As a typical example of using alkoxysilane, Ishida et al. obtained cyclohexylsilanetriol by mixing cyclohexyltrimethoxysilane in an aqueous solution of acetic acid and stirring for 2 hours at room temperature [J. Polym. Sci. 1979, 17, 1807]. In addition, Korkin et al. reported that they obtained phenylsilanetriol with a yield of 68% by adding phenyltrimethoxysilane dropwise to an acetic acid aqueous solution, stirring for 4 hours while maintaining temperature at 5-10° C. and removing impurities from the resulting white solid through filtration [J. Organomet. Chem. 2003, 686, 313]. However, the method of using alkoxysilane is limited in that the resultant silanetriol should be insoluble in water.