Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[C:7](=O)[C:6]=2[CH:22]=1.C.OS(O)(=O)=O>O1CCOCC1.C(O)C.[Pd]>[OH:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[CH2:7][C:6]=2[CH:22]=1
Reactant: COc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(C2COc3cc(O)c(O)cc3C2)cc1OC

Procedure:
6,7-Dihydroxy-3-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one [Indian J. Chem. Sect. B 19B, 82 (1980) and Indian J. Chem. Sect. B 15B, 1049 (1977)] (25 g) in a mixture of dioxane and ethanol 1:1 (1250 ml) is hydrogenated for 8 days at normal pressure and room temperature over palladium 10% on active charcoal (2.5 g) in the presence of concentrated H2SO4 (2.5 ml). After filtration of the catalyst, the filtrate is evaporated under reduced pressure to a volume of about 50 ml and diluted with water till turbidity appears. After cooling the solution, a solid precipitates. It is filtered off and recrystallized from ethanol. The product is dried in vacuo to constant weight to yield 3,4-dihydro-6,7-dihydroxy-3-(3,4-dimethoxyphenyl)-2H-1-benzopyran, m.p. 153°.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].I[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(N(CC)CC)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Nc1ccccc1I
Reactant: C#CCCCC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
32 mg of copper iodide and 140 mg of bis(triphenylphosphine) palladium chloride, then 2.3 ml of 1-hexyne were added to a solution of 4.4 g of 2-iodoaniline in 100 ml of triethylamine and the mixture was stirred for 15 hours at ambient temperature. After evaporation to dryness, the residue was taken up in ether and the insoluble part was filtered out and washed with ether. The filtrate was evaporated to dryness and the residue was chromatographed on silica (eluant: hexane-ethyl acetate (9-1)) to obtain 3.27 g of the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH2:13](Cl)Cl>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:13])=[O:7]
Reactant: O=C(O)c1ccc[nH]1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pyrrole-2-carboxylic acid (5 g.) was combined with 200 ml. of methylene chloride and 20 ml. of thionyl chloride and refluxed for 2 hours. The solution was evaporated to dryness in vacuo and the resulting acid chloride converted to ester by addition of 30 ml. of methanol and 20 minutes stirring at room temperature. Ether (50 ml.) was added and the mixture extracted with 50 ml. of water. The ether phase was dried over anhydrous sodium sulfate, filtered and evaporated to yield methyl pyrrole-2-carboxylate (5 g., m.p. 69°-71° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9]Br>ClCCl.O>[Br:9][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[OH:8]
Reactant: BrBr
Reactant: Oc1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: Oc1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
A solution of 5.03 gm (39.1 mMol) 3-chlorophenol in 20 mL dichloromethane was cooled in an ice bath as 6.25 gm (39.1 mMol) bromine were added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with water, the phases separated, and the organic phase dried over magnesium sulfate. The residue was subjected to silica gel chromatography, eluting with 3:2 dichloromethane:hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 2.04 gm (25%) of 2-bromo-5-chlorophenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-ethoxycarbonylnitrobenzene (5.0 g) in methanol (75 ml) was added palladium on carbon (0.5 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the desired compound (4.6 g, yield 99%) as a gray oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Product: COc1ccc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (87 mg, 0.3 mmol) and 4-chloro-6-methoxyquinazoline (59 mg, 0.3 mmol) as described in Example 46 and its corresponding hydrochloride salt was prepared as described in Example 4B Step 2 to give 1-(5-tert-butyl isoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-ylthio)phenyl)urea as the mono-hydrochloride (76 mg, 0.15 mmol, 50%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.80 (s, 1H), 7.95 (d, 1H), 7.87 (s, 1H), 7.71 (dd, 1H), 7.55 (d, 1H), 7.49-7.42 (m, 2H), 7.29 (d, 1H), 6.50 (s, 1H), 4.00 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.O1CCOCC1.C(Cl)[Cl:31]>Cl>[ClH:31].[ClH:31].[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3([NH2:7])[CH2:10][CH2:9]3)=[N:12][CH:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nc2)cn1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C3(N)CC3)nc2)cn1
Reaction time: 8 h

Procedure:
To a solution of {1-[5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (1.1 g, 3.5 mmol) in CH2Cl2 (15 mL), 4.0M HCl in dioxane (4.35 mL, 17.5 mmol) was added. After stirring overnight, more 4.0M HCl in dioxane (4.35 mL, 17.5 mmol) was added to the solution. After another 12 hours, the solution was concentrated in-vacuo to yield 800 mg of the title compound.
Reaction SMILES: [Br-].[CH3:2][C:3]([CH3:15])=[CH:4][CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:14])[CH3:13])[CH:7]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:2][CH:3]([CH3:15])[CH:4]=[CH:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8]([C:12]([CH3:13])=[O:14])=[CH:7]1
Reactant: [H][H]
Reactant: CC(=O)c1ccc[n+](CC=C(C)C)c1
Agent: [Pd]
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C1=CN(C=CC(C)C)CCC1

Procedure:
1-(3-methyl-2-butenyl)-3-acetyl-pyridinium bromide (27.0 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in ethyl alcohol (50 ml) over 5% palladium on carbon (5 g) was hydrogenated at room temperature and pressure until two molar equivalents of hydrogen was taken up. The catalyst was removed by filtration and the filtrate concentrated at reduced pressure. The semi-solid residue was diluted with diethyl ether (75 ml), the solid removed by filtration and the filtrate concentrated under reduced pressure to leave a pale oil which solidified on standing. Recrystallisation from ethanol/water gave the product, methyl 1-(3-methylbutenyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (4) as a pale yellow crystalline solid m.p. 76°-78° C.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
3-[4-(4-Nitrophenoxy)pyridin-2-yl]-1,1-dimethylurea (607 mg) was dissolved in tetrahydrofuran (20 ml)-methanol (20 ml), and then 10% palladium carbon (236 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (529.5 mg, 96.7%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][C:21]1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH:38]1([CH:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)CN)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][CH2:21][CH:43]([CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:19])(=[O:15])=[O:16])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: NCC(c1ccccc1)C1CCCC1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)CC(=O)NCC(c1ccccc1)C1CCCC1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with 2-cyclopentyl-2-phenylethylamine, mp 168°-170° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][S:17][C:4]1[N:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Nc2ccccc2)c(C=O)c(-c2ccccc2)n1
Yield: 69.8 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhydrous K2CO3 (443 mg, 3.21 mmol, 3 eq) followed by phenylboronic acid (196 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphosphine)-palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The reaction mixture was then heated under reflux for 24 h and cooled 23°, the layers were separated, EtOAc (50 mL), followed by H2O (10 mL), was added, the organic layer was separated, washed with sat'd aqueous (hereinafter “aq”) NaCl, dried (MgSO4) and filtered. The yellow solution was then evaporated. Product was purified by column chromatography or by crystallization from 10 mL of isopropanol: H2O (2:1) to give 240 mg (70% yield) of pure 2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.60 (s, 3H), 7.22 (m, 1H), 7.35-7.81 (m, 9H), 9.89 (s, 1H), 11.31 (br s, 1H), LC MS (m/e)=322 (MH+).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][N:30]=[C:22]3[C:21]3(OCCC[O:33]3)[C:20]=2[CH:19]=1)(=[O:17])=[O:16])C1C=CC=CC=1.CS(O)(=O)=O.[NH4+].[OH-]>>[OH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][C:28]([CH3:31])([CH3:32])[CH2:29][N:30]=[C:22]3[C:21](=[O:33])[C:20]=2[CH:19]=1)(=[O:16])=[O:17]
Reactant: CC1(C)CN=C2N(C1)c1ccc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)cc1C21OCCCO1
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4CO)ccc3N2C1
Yield: 78 %

Procedure:
To neat 8′-({(2S)-2-[(benzyloxy)methyl]pyrrolidin-1-yl}sulfonyl)-3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole] (0.500 g, 0.951 mmol) was added methane sulfonic acid (24 mL) all at one time at room temperature. After 5 hr the reaction mixture was poured onto ice and basified to pH 11.2 by the drop-wise addition of concentrated NH4OH keeping the temperature below 5° C. The reaction was extracted with EtOAc (5×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (94.75/3.5/1.75) to give the title compound as a bright orange solid (0.28 g, 68% yield). A 100 mg sample was dried at 63° C. in vacuo to give the analytically pure sample. Anal. Calc'd for; C18H23N3O4S: C, 57.28; H, 6.14; N, 11.13. Found: C, 57.05; H, 5.99; N, 10.79. NMR (400 MHz, DMSO-d6): consistent. MS: (ES+) m/z 378 [M+H]. m.p.: 91-96° C. dec.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:38])[CH2:23][C:24]=1[CH:25]=[CH:26][O:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:20]([NH:39]C(OC(C)(C)C)=O)[C:19]2=[O:47])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C>[NH2:39][CH:20]1[C:19](=[O:47])[N:18]2[CH:21]1[S:22](=[O:38])[CH2:23][C:24]([CH:25]=[CH:26][O:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[C:17]2[C:15]([O:14][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3S(=O)C2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3S(=O)C2)cc1
Yield: 60.8 %

Procedure:
A solution of the E form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (54.3 g) and hydrated p-toluenesulphonic acid (30.4 g) in acetonitrile (1.4 liters) is stirred at 35° C. for 2 hours. The mixture is concentrated to dryness at 30° C. under 20 mm Hg (2.7 kPa), the residue is taken up in ethyl acetate (1 liter) and the mixture is washed with a semi-saturated solution of sodium bicarbonate (2×500 cc) and a semi-saturated solution of sodium chloride (2×500 cc), dried over sodium sulphate and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is triturated in ether (200 cc). This yields the E form of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (28.13 g) in the form of a light brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>C1C=CC=CC=1.CO.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>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[C:10]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(I)nn2C(=O)OC(C)(C)C
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: CO
Solvent: c1ccccc1
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(-c1ccccc1Cl)nn2C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-3-iodo-4-methyl-5-oxo-4,5-dihydro-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester (18 mg) in benzene (1.3 mL) and methanol (0.26 mL) was added 1 M aqueous solution of sodium carbonate (76 μL, 2 eq), 2-chlorophenylboronic acid (12 mg, 2 eq), and Pd(PPh3)4 (13 mg, 0.3 eq). The mixture was purged with argon, heated at reflux for 2 hours, cooled to room temperature, and diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed with brine (1×25 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product ((M+H)+=488) which was used without purification for the following step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH3:25])[CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)=[CH:10][CH:9]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.C[C:29]([N:31](C)C)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[CH3:27][O:26][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[N:12][C:11]([N:14]([CH3:25])[CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)=[CH:10][CH:9]=1)[C:29]#[N:31]
Reactant: CC(=O)N(C)C
Reactant: COc1cc(Cl)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
To a flask containing 6-(4-chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (1.1 g, 2.88 mmol), Pd2(dba)3 (0.26 g, 0.29 mmol), dppf (0.32 g, 0.58 mmol), zinc dust (75 mg, 1.15 mmol), and zinc cyanide (1.0 g, 8.63 mmol) was added DMA (8.99 mL). The reaction was stirred at 150° C. for 18 h. The crude reaction mixture was cooled to RT, then diluted with EtOAc and filtered through celite. The filtrate was washed with 1 M NaOH (4×), water (6×), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified via column chromatography to give 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile (1.1 g). LCMS Rt=1.02 min (condition B); MS (M+1)=380.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.09 (d, J=8.1 Hz, 1H), 7.80 (d, J=9.6 Hz, 1H), 7.38 (dd, J=7.8, 1.5 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 6.81 (d, J=9.6 Hz, 1H), 5.12-5.28 (m, 1H), 3.90 (s, 3H), 3.00 (s, 3H), 1.71 (dd, J=12.5, 3.4 Hz, 2H), 1.42-1.51 (m, 2H), 1.38 (s, 6H), 1.23 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[Cl:20][C:21]1[C:22]([CH2:31][NH2:32])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([CH2:31][NH:32][C:11](=[O:13])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1[N+](=O)[O-])NCc1ncc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-nitrophenylacetic acid (0.36 g) in dry toluene (5 ml) at room temperature was added phosphoryl chloride (0.37 g) and stirring was continued overnight. Meanwhile a solution of the amine was prepared, (3-Chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.49 g) in dry toluene (5 ml) and triethylamine (1.23 g) was stirred at room temperature for 1 hour and then filtered. The solid was washed with dry toluene and the combined filtrates were added dropwise to the above suspension of acid chloride with ice-cooling. After addition, the mixture was stirred at room temperature overnight. Dichloromethane was added and the mixture was washed with water. The aqueous layer was separated and back-extracted with dichloromethane. The combined organic extracts were washed with saturated sodium bicarbonate solution, then brine, then dried (MgSO4), and the solvent removed. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/light petroleum (b.p. 40-60° C.) to give the title product, m.p. 123-4° C.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[OH:28])[C:21]([NH:23][NH2:24])=[O:22]>>[OH:16][CH2:15][CH2:14][CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH:1]=[N:24][NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][C:27]([OH:28])=[C:18]([Cl:17])[CH:19]=2)=[CH:4][CH:5]=1
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: O=Cc1ccc(CCCO)c2ccccc12
Product: O=C(NN=Cc1ccc(CCCO)c2ccccc12)c1ccc(O)c(Cl)c1

Procedure:
This compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of 1-formyl-4-(3-hydroxypropyl) naphthalene from step B and 3-chloro-4-hydroxy benzoic acid hydrazide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:5][C:6](SC)=[N:7][CH:8]=1>C(O)C.N.[Ni]>[OH:1][CH2:2][C:3]1[C:4]([C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cc(-c2nc(SC)ncc2CO)cc(OC)c1OC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1cc(-c2ncncc2CO)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
5-Hydroxymethyl-2-methylthio-4-(3,4,5-trimethoxyphen yl)pyrimidine (1.75 g) was dissolved in a mixed solvent of ethanol (50 mL) and aqueous ammonia (5 mL). Raney nickel (R=100, wet type, 17.0 g) was added to the solution, and the mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1) to obtain the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(OCCCN2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[3-(4-hydroxymethylphenoxy)propyl]piperidine (5.617 g) in dichloromethane (50 mL), cooled at a temperature close to 0° C., is added dropwise thionyl chloride (3 mL). The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure. The residue is crystallized in diethyl ether to give 1-[3-(4-chloromethylphenoxy)propyl]piperidine as an off white solid used without further purification.