Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[CH2:18]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[OH:11])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1ccc(Oc2ccccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=CCc1cc(Oc2ccccc2Cl)ccc1O
Temperature: 230 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 4-(2-chlorophenoxy)phenol (15 g), allyl bromide (12.5 g) and potassium carbonate (14 g) in methyl isobutyl ketone (100 ml) was refluxed under heating for 3 hours. After cooling, the reaction mixture was filtered, and the filtrate was evaporated. The residue was dissolved in diethyl ether, washed with dil. aqueous sodium hydroxide and water, dried and evaporated. The oily residue was stirred in a oil bath at 230° C. for 2 hours and distilled to give 2-allyl-4-(2-chlorophenoxy)phenol (14.7 g). bp 189°-192° C./3 mmHg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].Cl.Cl.[CH3:18][N:19]([CH3:27])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (336 mg, 1.6 mmol) to afford the desired product (156 mg, 38%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 10.88 (br s, 1H), 8.94 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 5.07-4.92 (m, 1H), 2.67 (s, 3H), 2.34 (s, 6H), 2.39-2.32 (m, 2H), 2.31-2.22 (m, 1H), 2.07-1.99 (m, 2H), 1.56-1.35 (m, 4H); ESI MS m/z 347 [M+H]+
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:7]=2)[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(-c3ccccc3)n2)cc2cn[nH]c12
Temperature: 140 °C
Yield: 81.7 %

Procedure:
To a microwave tube charged with (±)-N-(1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (24.6 mg, 0.0418 mmol, 1.0 equiv) was added phenyl boronic acid (7.1 mg, 0.0585 mmol, 1.4 equiv), Pd(PPh3)4 (4.8 mg, 0.1 equiv), toluene (1 mL), ethanol (0.2 mL), and potassium carbonate solution (2M, 0.085 mL). The vial was sealed and heated by microwave at 140° C. for 30 min. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. Flash column chromatography (10% methanol/methylene chloride) afforded the desired product (20 mg, 81.6%) as an off-white solid: MS (ESI) [M+H]+=586. 1H-NMR (400 MHz, CDCl3) δ 8.00-7.86 (m, 3H), 7.65-6.82 (m, 12H), 6.74 (d, J=7.2 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.32 (br., 1H), 5.35-5.20 (m, 1H), 4.62-4.48 (m, 1H), 4.30-4.08 (m, 4H), 3.40 (dd, J=13.2 and 4.2 Hz, 1H), 3.13 (dd, J=13.2 and 8.4 Hz, 1H), 3.02-2.83 (m, 2H), 2.42 (s, 3H), 1.80-1.55 (m, 4H). HPLC tR=1.51 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:34]=[CH:35][CH:36]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[N:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6].O>FC(F)(F)C([O-])=O>[Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:34]=[CH:35][CH:36]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[CH:24][NH:23][N:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CN3CCN(C(=O)c4cccc(Cl)c4F)CC3)n2)n1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cccc(Nc3cc[nH]n3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
18 mg of (6-((4-(3-Chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridin-2-amine was dissolved in 900 μl of trifluoroacetate and 100 μl of water followed by stirring at room temperature for 5 hours. The reaction solution was concentrated in vacuo, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate, water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC#N>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:23]
Reactant: C1CNCCNC1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCCCN1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
Sodium carbonate (2.12 g) was added to the solution of homopiperazine (10.0 g; 5 eq.) and ethyl 5-bromovalerate (4.18 g; 1 eq.) in CH3CN (120 mL). The reaction was stirred at room temperature for 6 h. The reaction mixture was filtered thru a celite pad. The filtrate was concentrated. The remaining residual was dissolved in CHCl3 (120 mL), washed by H2O (50 mL×3) and brine (50 mL×1), dried by Na2SO4 and concentrated to give 5-[1,4]diazepan-1-yl-pentanoic acid ethyl ester (4.0 g), which was carried on for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.09 (q, 2H, J=7.0 Hz), 2.90 (m, 4H), 2.63 (m, 4H), 2.47 (t, 2H, J=7.0 Hz), 2.29 (t, 2H, J=7.0 Hz), 2.07 (bs, 1H), 1.73 (m, 2H), 1.60 (m, 2H), 1.48 (m, 2H), 1.22 (t, 3H, J=7.0 Hz).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]([O:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1)([CH3:10])[CH3:9].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>C(OCC)(=O)C>[CH:8]([O:11][C:12]1[N:16]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[N:15]=[C:14]([NH2:17])[CH:13]=1)([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)Oc1cc(N)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(N)nn1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
Sodium hydride (60%, 425 mg, 10.63 mmol) was added to a DMF (mL) solution of 5-isopropoxy-1H-pyrazole-3-amine (1.5 g, 10.63 mmol) at −18 degrees, and the mixture was stirred for 30 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (1.89 mL, 10.63 mmol) was added dropwise, and stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate, and washed once with distilled water, and once with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the title compound (462 mg, 16%).
Reaction SMILES: [CH3:1][C:2]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C.C(Cl)(Cl)Cl>[CH3:6][C:2]([CH:7]1[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]1)([CH3:1])[C:3]([O:5][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C(=O)O)C1CCC(=O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 2-methyl-2-(4-oxocyclohexyl)propanoic acid (0.184 g, 1 mmol) and DIPEA (0.192 mL, 1.100 mmol) in acetonitrile (1 mL) and CHCl3 (1 mL) was added benzyl bromide (0.131 mL, 1.100 mmol) and the mixture was stirred at rt overnight. The reaction mixture was evaporated to dryness and purified by silica gel FCC (0-5% EtOAC in DCM) to afford benzyl 2-methyl-2-(4-oxocyclohexyl)propanoate as a clear oil (184 mg), which was dissolved in CH2Cl2 (2 mL) was treated with Deoxo-Fluor® (0.442 mL, 2.40 mmol), followed by the addition of EtOH (5.8 mL). The resulting yellowish solution was stirred at rt overnight. The reaction mixture was diluted with sat. NaHCO3 and EtOAc. The organic phase was separated and washed with water, sat. NaCl, dried over anhydrous MgSO4, filtered and dried to yield a yellow oil. The crude product was purified by silica gel FCC (1:1 hexane-DCM) to afford benzyl 2-(4,4-difluorocyclohexyl)-2-methylpropanoate as a clear oil (143 mg) which was hydrogenated (0.053 g of 10% Pd—C, EtOAc) under balloon pressure for 4 h. The suspension was filtered and evaporated to dryness to afford Cap P-21. 1H NMR (500 MHz, CDCl3) δ ppm 2.08-2.23 (2H, m), 1.64-1.85 (5H, m), 1.36-1.54 (2H, m), 1.12-1.29 (6H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[NH:10][C:9]=2[C:8]([O:22]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
2-(3-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (0.95 g, 8.98 mmol) obtained in step 2 was dissolved in toluene, aluminum chloride (1.5 g, 11.25 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (0.81 g, 2.64 mmol) in a yield of 80%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[C:30]3[NH:32][CH2:33][C:34]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:29]3=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:32]3[C:30]4[C:29](=[CH:28][CH:27]=[C:26]([N:23]5[CH2:22][CH2:21][O:20][CH2:25][CH2:24]5)[CH:31]=4)[C:34]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:33]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepare according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (75 mg, 0.27 μmol), 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (75 mg, 0.27 mmol) and a 4.0M solution of HCl in 1,4-dioxane (0.014 mL, 0.055 mmol). After purification 1-(7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.91 (1H, d, J=2.3 Hz), 8.73 (1H, dd, J=4.9, 1.8 Hz), 8.01 (1H, dt, J=7.8, 2.2 Hz), 7.76-7.89 (2H, m), 7.48 (1H, dd, J=8.0, 4.9 Hz), 7.27 (1H, dd, J=17.6, 2.7 Hz), 7.14 (1H, d, J=8.2 Hz), 6.36 (1H, dd, J=8.2, 2.3 Hz), 5.61 (1H, d, J=2.3 Hz), 4.00-4.09 (2H, m), 3.91-3.99 (2H, m), 3.70-3.79 (4H, m), 3.50-3.61 (2H, m, J=12.0, 12.0, 2.5, 2.3 Hz), 2.90-3.02 (4H, m), 2.30 (3H, s), 2.10-2.24 (2H, m), 1.89 (1H, dd, J=13.7, 2.3 Hz), 1.75-1.82 (1H, m). Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[O:12]=[C:13](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[C:4]12[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:2][C:13](=[O:12])[O:7][C:5]2=[O:6]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccccc2c(=O)o1

Procedure:
7.5 g of 2-amino benzoic acid hydrochloride was mixed with 10 ml of diphosgene and the mixture was stirred in 150 ml of dioxane for 40 minutes at reflux. The resulting mixture was cooled and filtered. Yield: 5.7 g of title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:26]=[CH:25][CH:24]=[CH:23][C:4]=2[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[N:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=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>[CH3:22][C@H:9]1[N:8]([C:5]2[C:4]3[CH:23]=[CH:24][CH:25]=[N:26][C:3]=3[C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)=[N:7][N:6]=2)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ncccc12
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+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2ncccc12

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (180 mg, 489 μmol), 2 M sodium carbonate (489 μl, 979 μmol), tetrakis(triphenylphosphine)palladium (28 mg, 24 μmol), and 4-trifluoromethylphenylboronic acid (139 mg, 734 μmol) afforded (R)-(3-methyl-4-(8-(4-(trifluoromethyl)phenyl)pyrido[3,2-d]pyridazin-5-yl)piperazin-1-yl)(phenyl)methanone 86 after chromatographic purification. MS 477.2 (calc'd) 478.1 (M+H, found).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH:10]2[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:15]([NH:22][CH2:23][CH2:24][OH:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[CH2:15]([N:22]([CH2:23][CH2:24][OH:25])[C:12]([CH:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:11]1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(O)C1OC1c1ccc(Cl)c(Cl)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C1OC1c1ccc(Cl)c(Cl)c1)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a mixed solution of (2RS,3SR)-3-(3,4-dichlorophenyl)oxirane-2-carboxylic acid (50.0 g) and 2-(benzylamino)ethanol (38.9 g) in THF (700 mL)-methanol (100 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (71.2 g), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (42.2 g).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][CH:12]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>CO.O>[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][S:13](=[O:2])[CH:12]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCC(O)CCN1C(=O)CSC1CCCCCCC(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Temperature: 0 °C

Procedure:
Sodium metaperiodate (0.75 g., 3.5 millimole) is added to a cold (0°-5° C.) solution of 7-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]heptanoic acid (1.24 g., 3.44 millimole) in methanol-water (5:4; v:v; 18 ml.). The resulting mixture is stirred and allowed to slowly warm to 25° C. (as the ice bath melts, etc.) over 16 hours. After removing the precipitated solid via filtration, the filtrate is diluted with cold water and extracted twice with chloroform. The organic extract is washed with saturated aqueous brine, dried over magnesium sulfate, filtered, and evaporated in vacuo leaving an oily residue which is chromatographed on silica gel (20 g.). Elution with chloroform-acetic acid (25:1; v:v) provides the title compound as a viscous, essentially colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[S:9][CH:10]=1)=O)C.[BH4-].[Na+].Cl>CCO>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CCOC(=O)c1csc(-c2ccc(C)cc2[N+](=O)[O-])n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2nc(CO)cs2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
2-(4-Methyl-2-nitro-phenyl-thiazole-4-carboxylic acid ethyl ester (292 mg, 1 mmol) was dissolved in 5 mL of absolute EtOH at room temperature in an open flask. Sodium borohydride (1 mmol, 38 mg) was added portionwise over several hours and the reaction was monitored by TLC (EtOAc:hexanes 2:3). After completion of the reaction, 2N HCl was added carefully with stirring. After 15 min, the clear yellow solution was concentrated on the rotavap, and the crude mixture was partitioned between EtOAc (60 mL) and water (60 mL). The organics were isolated and washed with sat NaHCO3 and 60 mL of sat NaCl. The organics were dried over MgSO4, filtered and concentrated to provide an orange solid as the desired material.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:31]([F:34])([F:33])[F:32])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH:28]([F:30])[F:29])[CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>O.C(OCC)(=O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:7]=[C:6]([Cl:5])[CH:11]=[C:10]([Cl:12])[CH:9]=3)([C:31]([F:33])([F:34])[F:32])[O:17][N:16]=2)=[CH:19][C:20]=1[O:27][CH:28]([F:29])[F:30]
Reactant: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Yield: 90.8 %

Procedure:
In a mixture of 5.0 mL of water, 1.0 mL of acetic acid and 1.22 g of reduced iron, a solution of 2.0 g of 5-(3,5-dichlorophenyl)-3-(3-difluoromethoxy-4-nitrophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 15 mL of ethyl acetate was added dropwise at 75° C. under stirring with heating. After the completion of the addition dropwise, it was stirred at the same temperature for 2.5 hours. After the completion of the reaction, the reaction mixture was subjected to hot filtration through Celite, 20 ml of water was added in the filtrate, extracted with ethyl acetate (20 ml×2). The combined organic phases were washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.7 g of the crude aimed product as yellow resinous substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[NH2:15][C@H:16]1[CH2:21][N:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](=[O:30])[CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22][N:20]1[C:19](=[O:30])[CH2:18][CH2:17][C@@H:16]([NH:15][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:21]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCC(=O)N(OCc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCC(=O)N(OCc3ccccc3)C2)cn1
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
Ethyl (2E)-3-(5-chloro-2-Pyrazinyl)acrylate (250 mg, 1.18 mmol) and (5R)-5-amino-1-(benzyloxy)-2-piperidinone (388 mg, 1.86 mmol) were combined in 1,4-dioxane (4 mL) at ambient temperature. To this solution were added palladium(II) acetate (18 mg, 0.8 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (46 mg, 0.1 mmol) at the same temperature and the mixture was stirred for 5 minutes. To the resulting mixture was added cesium carbonate (536 mg, 1.86 mmol) and the mixture was heated at 95° C. for 24 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3/methanol=95/1) to give ethyl (2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)acrylate (202 mg, 43%) as an amorphous solid.
Reaction SMILES: [F-].[Cs+].[C:3]([C:5]1[CH:6]=[C:7](OB(O)O)[CH:8]=[CH:9][C:10]=1[F:11])#[N:4].Cl[C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][N:26]=1)[C:20]([O:22][CH3:23])=[O:21]>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.COCCOC>[C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][N:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(OB(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1

Procedure:
Cesium fluoride and tetrakis(triphenylphosphine)palladium were added to a 1,2-dimethoxyethane solution of (3-cyano-4-fluorophenyl)boric acid and methyl 2-chloroisonicotinate, and the mixture was heated under reflux in an argon atmosphere to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.