Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>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.CN(C=O)C.CCN(CC)CC>[OH:7][C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[C:4][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CC(C)(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-pentyn-3-ol (75 mg, 0.75 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (25 mg) and CuI (12 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 66 mg, 31%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)=[O:42])[C:25]3[N:29]=[C:28]([O:30]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:40]=2)=[C:20]([CH3:49])[O:19][N:18]=1.Cl>C(OCC)C.C(O)C>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([OH:42])([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)[C:2]3[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=3[F:10])[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]=3[CH:40]=2)=[C:20]([CH3:49])[O:19][N:18]=1
Reactant: CCOc1nc2c(C(=O)c3cnccn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)c(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCOCC
Product: Cc1noc(C)c1-c1cc(C(O)(c2cnccn2)c2c(F)cc(F)cc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To 1-bromo-2,4,6-trifluorobenzene (0.01 ml, 0.12 mmol) in diethyl ether (0.5 mL) at −78° C. was added n-butyllithium (0.13 mL, 0.14 mmol, 1.6 M in hexanes). After 30 tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(pyrazine-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylate (36.6 mg, 0.08 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 90 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (1.5 mL) was added hydrochloric acid (0.20 mL, 0.79 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (35-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyrazin-2-yl)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=N/NC(N)=O)=[C:4]([N+:15]([O-])=O)[CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.[Rh]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:9][NH:15]2)=[CH:6][CH:7]=1
Reactant: NC(=O)N/N=C/Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.8 %

Procedure:
To a stirred suspension of (1E)-(4-fluoro-2-nitrophenyl)ethanal semicarbazone (27.0 g, 0.110 mol) in THF (750 mL) in a 1 L bomb was added Rh/C %; 3.5 g, 0.002 mol Rh) slurried in toluene and Fe(OAc)2 (2.9 g, 0.017 mol). The bomb was charged with H2 to 50 atm and stirred at room temperature for 2 days. The reaction mixture was filtered through celite, washing with MeOH (150 mL). The filtrate was concentrated to give a black oil that was partitioned between DCM (500 mL) and water (300 mL). The layers were separated and the aqueous fraction was extracted with DCM (2×200 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and treated with flash silica to decolourise the solution. The mixture was filtered concentrated under reduced pressure, giving 12.9 g (87%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH2:15][C@H:14]([NH:25]C(=O)OC(C)(C)C)[C:13]2=[O:33])[CH2:10][CH2:9]1>ClCCl>[NH2:25][C@H:14]1[CH2:15][CH2:16][CH2:17][C@@H:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:12]([CH2:11][CH:8]2[CH2:9][CH2:10]2)[C:13]1=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](c2ccccc2)N(CC2CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCC[C@@H](c2ccccc2)N(CC2CC2)C1=O
Reaction time: 1 h
Yield: 106.4 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution tert-butyl (3S,7S)-1-(cyclopropylmethyl)-2-oxo-7-phenylazepan-3-ylcarbamate (144.1 mg, 0.40 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[N:5]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[N:3]=1.[I-].[K+].C(#N)C.C[Si](C)(C)Cl>CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: COc1cc(Cl)nc(CC(=O)N2CCc3c(F)cccc32)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Reaction time: 8 h
Yield: 59 %

Procedure:
2 g of 2-(4-chloro-6-methoxypyrimidin-2-yl)-1-(4-fluoro-2,3-dihydroindol-1-yl)ethanone (example 17b, step 1b), potassium iodide (3.1 g), 30 ml of acetonitrile and 2.03 g of trimethylchlorosilane are placed in a reactor suitable for microwave-heating. The reactor is closed and irradiated for 30 minutes at 100° C. and then left overnight at A.T. The reaction medium is diluted with EtOAc and then washed twice with water and then with brine. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. The product obtained is chromatographed on silica. Elution is then carried out with dichloromethane/methanol (from 100/0 to 95/5). The fractions containing the expected product are evaporated under reduced pressure. The compound obtained is triturated from methanol, filtered and dried. 2-(4-Chloro-6-oxopyrimidin-2-yl)-1-(4-fluoro-2,3-dihydroindol-1-yl) ethanone is isolated (1.13 g); yield=59% (LCMS ES+ retention time Tr (min)=1.04; [M+H]+: m/z 308).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:18][CH2:19][C:20](O)=[O:21])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:7][C:6]1=[O:23])[CH3:4].CC[N:28]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:18][CH2:19][C:20]([NH2:28])=[O:21])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:7][C:6]1=[O:23])[CH3:4]
Reactant: C[C@H](N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (50 mg, 0.144 mmol), EDCI (55 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), and DIEA (90 mg, 0.07 mmol) were dissolved in CH2Cl2 (10 mL) under ice bath. The mixture was stirred under an NH3 atmosphere overnight. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC to give 3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide (15 mg, 30%). LC-MS Method 1 tR=2.027, min, m/z=351.1; 1H NMR (CDCl3) 0.73 (s, 9H), 1.12 (d, 3H), 1.89-1.98 (m, 1H), 2.01-2.12 (m, 1H), 2.22-2.38 (m, 3H), 2.48-2.52 (m, 1H), 2.71 (m, 1H), 3.18 (m, 1H), 4.46 (m, 1H), 5.29 (s, 1H), 5.53 (s, 1H), 7.07 (m, 2H), 7.29 (m, 2H)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])=[O:11].C(Cl)CCl.[NH3:26]>CN(C1C=CN=CC=1)C.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:26])=[O:16])=[O:11]
Reactant: O=C(Nc1ncccc1C(=O)O)c1cc2ccccc2s1
Reactant: N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1cccnc1NC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 2-[(1-benzothien-2-ylcarbonyl)amino]nicotinic acid (112 g, 4.0 mmol), EDC (2.3 g, 12.0 mmol) and DMAP (1.46 g, 12.0 mmol) in anhyd dichloromethane (50 mL) was stirred at room temperature for 2 h. To this mixture was added 40% aqueous ammonia (4.0 mL), and the resulting solution stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid was washed with satd NH4Cl solution, NaHCO3 solution, and water. The solid was dried to give product as white powder (0.92 g, 77%). HPLC/MS: (M+H)+298.15 m/z Retention time (LC-MS)=2.44 min. 1H NMR (DMSO-D6): 12.25 (1H, s); 8.54(1H, m); 8.21(1H, s); 8.18(1H, d); 8.07(2H, m); 7.52(2H, m); 7.32(1H, m).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[S-:16][C:17]#[N:18].[NH4+]>CO>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([S:16][C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
To a three-necked, round bottom 5 L flask, equipped with a mechanical stirrer, gas inlet, thermometer and gas inlet, thermometer and gas outlet, was added 2,6-di-tert-butylphenol (474 g, 2.30 mole), ammonium thiocyanate (76.12 g, 4.83 mole) and methanol (1200 ml). The reaction mixture was stirred and cooled to 0° C. in an ice/salt bath. Maintaining the temperature at 0° to 10° C., chlorine gas was slowly bubbled through the mixture for about 1 hour whereupon the reaction mixture was a heterogeneous yellow color. Ammonia was then bubbled through the reaction for about 1-1/2 hours, maintaining the reaction mixture at a temperature of between 0° to 10° C. The reaction was stirred for an additional hour at 0° C., poured into 2 L of cold distilled water and refrigerated overnight. The aqueous phase was decanted and the solid taken up in methanol, precipitated from water, filtered and dried for 2 days over phosphorous pentoxide. The resulting gummy yellow solid was recrystallized from pentane and dried in vacuo to yield the product as a white powder, m.p. 61.5°-63° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([Sn](CCCC)(CCCC)CCCC)[CH:6]=[CH:5][N:4]=1.Br[C:23]1[N:28]=[C:27]([C:29]2[N:33]3[N:34]=[C:35]([N:38]4[CH2:42][CH2:41][CH2:40][C@@H:39]4[C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=4)[CH:36]=[CH:37][C:32]3=[N:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=1>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>[F:49][C:45]1[CH:44]=[C:43]([C@H:39]2[CH2:40][CH2:41][CH2:42][N:38]2[C:35]2[CH:36]=[CH:37][C:32]3[N:33]([C:29]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:7]5[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=5)[N:28]=4)=[CH:30][N:31]=3)[N:34]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(Br)n4)n3n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2cccc(-c3cnc4ccc(N5CCC[C@@H]5c5cccc(F)c5)nn34)n2)n1
Temperature: 110 °C

Procedure:
In step 14-1, 2-(methylthio)-4-(tributylstannyl)pyrimidine (4.3 g, 13.2 mmol) and Pd(PPh3)4 (196 mg, 0.17 mmol) were added to a solution of (R)-3-(6-bromopyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (14-1) (1.5 g, 3.4 mmol) in toluene (35 mL). The mixture was degassed using N2 for 15 minutes and then heated at 110° C. for 2 hours. All the solvents were removed. The resulting mixture was purified by column chromatography (silica gel, EtOAc/CH3OH, 0 to 10% gradient) to give (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine (14-2) as a light-yellow foam. LC/MS: 484.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>C1C=CC=CC=1>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]1)=[O:32]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: CC1CCN(C(=O)Cl)CC1
Agent: CN(C)c1ccccn1
Solvent: c1ccccc1
Product: CC1CCN(C(=O)Oc2ccc3oc4ccccc4c3c2)CC1
Yield: 104.2 %

Procedure:
A mixture of 2-hydroxydibenzofuran (10.0 g, 54.3 mmol), dimethylaminopyridine (DMAP) (7.3 g, 59.8 mmol) and 4-methyl-1-piperidinecarbonyl chloride (8.8 ml, 59.7 mmol) in 200 mL of benzene was refluxed under nitrogen for 7 hours. The reaction was extracted with 1N HCl and then the organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 17.51 g of a light brown solid. Recrystallization of the solid from diisopropyl ether gave 10.82 g (64%) of the title compound as a light brown crystalline solid, mp 123°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Li+].O>CO>[CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc2[nH]c(-c3cccnc3OC)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ncccc1-c1cc2cc(C(=O)O)ccc2[nH]1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 2-(2-methoxypyridin-3-yl)-1H-indole-5-carboxylate (1.0 g, 0.354 mmol) in methanol (100 ml) was added lithium hydroxide (0.30 g, 1.25 mmol) and water (10 ml). The reaction was heated overnight at 80° C. The reaction was not complete so more lithium hydroxide (0.10 g, 0.42 mmol) was added and heating was continued for 4 hours. The reaction was allowed to cool and stir at room temperature overnight. The reaction was concentrated to about 15 ml and 1 g citric acid dissolved in 10 ml of water was added. The solid was filtered, washed with water (25 ml) and dried under high vacuum at 50° C. The desired product was obtained as a white solid and used in the next reaction without any purification (0.9 g, 94%). 400 MHz 1H NMR (DMSO-d6) δ: 12.56 (bs, 1H), 11.69 (s, 1H), 8.30-8.12 (m, 3H), 7.75 (dd, J=1.6 Hz, 8.5 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.24-7.09 (m, 2H), 4.06 (s, 3H). LCMS: 269 [M+H]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35]Cl)[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH:30]=1
Reactant: ClCc1cc(Cl)ccn1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cc(Cl)ccn4)cc3)no2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To 4-(5-(6-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 177-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.9 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of the solid obtained above and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (13.3 mg, 0.08 mmol) described in Manufacturing Example 51-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (7.2 mg, 25%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[N:24]=[C:25]2[N:29]([C:30]=1[S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:27][S:26]2>>[Cl:22][C:23]1[N:24]=[C:25]2[N:29]([C:30]=1[S:31]([N:1]1[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]1)(=[O:33])=[O:32])[CH:28]=[CH:27][S:26]2
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(S(=O)(=O)c3c(Cl)nc4sccn34)CC1)O2

Procedure:
Compound 77 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl chloride and conditions outlined in procedure P. M.p.=265-267° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.08-8.05 (m, 1H), 7.87-7.84 (m, 1H), 7.61-7.50 (m, 3H), 7.33-7.29 (m, 1H), 3.66-3.60 (m, 2H), 3.11 (s, 2H), 3.02-2.95 (m, 2H), 2.12-2.06 (m, 2H), 1.95-1.84 (m, 2H); LCMS: 522 [M+H].
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH3:12][CH2:13][O:14][C:15](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:14][C:15](=[O:16])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[CH:23][CH:24]=1)[CH3:12]
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OCc2nc(C)c(C)nc2C)cc1
Temperature: 90 °C
Yield: 76.7 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (2.15 g, 0.01 mol), p-hydroxyl ethyl cinnamate (2.30 g, 0.012 mol), anhydrous potassium carbonate (2.76 g, 0.02 mol), and DMF (50 mL) into a 100 mL three-necked bottle in turn, heating to 90° C., stifling to react for 10 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.5), filtering to obtain filtrate, adding 40 mL water, extracting with chloroform (3×40 mL), incorporating the chloroform layer and wishing with water (2×30 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain 2.5 g white crystalloid of (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-phenyl)acrylic acid ethyl ester, a yield is 76.7%, m.p. 90-92° C.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]1[CH3:23])(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][C@H:18]1[CH3:23])(=[O:15])=[O:16]
Reactant: C[C@@H]1CNCCN1S(C)(=O)=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)Cl)CCN1S(C)(=O)=O
Temperature: 25 °C
Yield: 178.8 %

Procedure:
Second step: To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (1.17 g, 3.95 mmol) in CH2Cl2 (20 mL) at −78° C., was added a solution of (R)-1-methanesulfonyl-2-methyl-piperazine (1.76 g, 9.9 mmol) and pyridine (1.60 mL, 20 mmol) in CH2Cl2 (20 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo and flash chromatography (SiO2, EtOAc/H, 1:1) yielded 1.70 g (71%) of (R)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.I[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[C:19]([O:29][CH3:30])[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:29][C:19]1[CH:18]=[C:17]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[S:27][C:26]([NH2:28])=[N:25][N:24]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(I)ccc1-c1nnc(N)s1
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: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N)s1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a stirred suspension of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (137 mg, 0.660 mmol) and 5-(4-iodo-2-methoxyphenyl)-1,3,4-thiadiazol-2-amine (200 mg, 0.6 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (35 mg, 0.03 mmol) followed by a solution of Na2CO3 (191 mg, 1.801 mmol) in water (1 mL). The reaction was purged with nitrogen then heated at 80° C. for 18 hours. The reaction mixture was diluted with MeOH (20 mL), filtered through celite, and rinsed with DCM (20 mL). The filtrate was concentrated in vacuo to afford the crude product as an orange oily residue. The crude product was pre-absorbed onto silica gel and purified by flash chromatography using a 24 g silica cartridge, running a MeOH/DCM gradient to afford the title compound as a pale yellow solid (107 mg, 62% yield). LC-MS: Rt 0.81 min; MS m/z 288.1 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.36 (d, J=1.52 Hz, 1H), 7.28 (dd, J=8.08, 1.52 Hz, 1H), 7.13 (s, 2H), 3.99 (s, 3H), 3.88 (s, 3H).