Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.[Cl-].C(N=C=NCCC[NH+](C)C)C>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][NH:28][C:16](=[O:18])[CH2:15][C:13]2[CH:12]=[CH:11][C:9]3[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=3[CH:14]=2)=[O:26])=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CCOC(=O)c1cc2ccc(CC(=O)O)cc2s1
Agent: CCN=C=NCCC[NH+](C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(CC(=O)NNC(=O)c3ccc(OC)cc3)cc2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
To a solution of [2-(ethoxycarbonyl)-1-benzothien-6-yl]acetic acid (100 mg, 0.38 mmol) and 4-methoxybenzohydrazide (63 mg, 0.38 mmol) in 2 mL DMF was added 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropane-1-aminium chloride (91 mg, 0.47 mmol). The reaction was stirred at ambient temperature for 12 hours. The reaction mixture was loaded directly onto a reverse phase C18 column for purification to give 78 mg (49%) of the title compound as a white solid. LC/MS (EI): cal'd 413.1 (MH+), exp 413.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:22](=[O:23])[C:21]([C:24]([NH2:26])=[O:25])=[C:20]([OH:27])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:16]([C:17]2=[O:18])=[C:15]([OH:29])[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:3]>CC([O-])=O.CC([O-])=O.[Pd+2].CO>[CH3:1][N:2]([C@@H:4]1[C:22](=[O:23])[C:21]([C:24]([NH2:26])=[O:25])=[C:20]([OH:27])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:16]([C:17]2=[O:18])=[C:15]([OH:29])[C:14]2[C:9](=[C:10]([C:4]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:5]=3)[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:3]
Reactant: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(-c5ccccc5)c4C[C@H]3C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
7-iodosancycline, 150 mg (0.28 mM), Pd(OAc)2 and 10 mL of MeOH are added to a flask with a stir bar and the system degassed 3× using argon. Na2CO3 (87 mg, 0.8 mM) dissolved in water and argon degassed is added via syringe is added along with phenylboronic acid (68 mg, 0.55 mM) in MeOH that was also degassed. The reaction was followed by HPLC for 2 hours and cooled to room temperature. The solution was filtered, and dried to produce a crude mixture. The solid was dissolved in dimethylformamide and injected onto a preparative HPLC system using C18 reverse-phase silica. The fraction at 36-38 minutes was isolated, and the solvent removed in vacuo to yield the product plus salts. The salts were removed before extraction into 50:25:25 water:butanol:ethyl acetate and dried in vacuo. This solid was dissolved in MeOH and the HCl salt made by bubbling in HCl gas. The solvent was removed to produce the product in 42% yield as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-nitrophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (d, J=7.4, 1H), 8.27-8.21 (m, 2H), 8.04 (d, J=7.8, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.67 (d, J=8.6, 2H), 3.84-3.81 (m, 4H), 3.70 (s, 2H), 3.11-3.07 (m, 4H); MS (ESI−) M/Z 408 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]([NH:12]C(=O)CCl)([CH3:11])[CH3:10])=[CH:4][CH:3]=1.NC(N)=S>C(O)C.C(O)(=O)C>[ClH:1].[NH2:12][C:9]([CH3:11])([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH3:10]
Reactant: CC(C)(NC(=O)CCl)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: NC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2,3-bis(4-chlorophenyl)-1,1-dimethylpropyl]chloroacetamide (Step C, 1.3 g, 3.8 mmol) in ethanol (10 mL) and acetic acid (2 mL) was added thiourea (0.34 g, 4.5 mmol). The reaction was stirred at 80° C. overnight to give a white precipitate. The precipitate was removed by filtration and washed with ethanol (10 mL), and the filtrate was diluted with dilute aqueous sodium hydroxide and extracted with hexane (2×50 mL). The combined extracts were dried over sodium hydroxide, filtered, and concentrated to dryness, and the residue was taken up by hydrogen chloride in dioxane (4 M, 5 mL) and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): (free amine) δ 7.22-7.14 (m, 4H), 7.06 (d, 2H), 6.96 (d, 2H), 3.22 (dd, 1H), 2.95 (dd, 1H), 2.86 (dd, 1H), 1.16 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][OH:22].CN([CH:26]=[O:27])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[Cl:13][C:4]1[C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=[C:2]([CH:3]=1)[C:21]([O:27][CH3:26])=[O:22]
Reactant: Clc1cc(Br)cnc1OCC1CC1
Reactant: CO
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc(OCC2CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 5-bromo-3-chloro-2-(cyclopropylmethoxy)pyridine (3.00 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (470 mg), triethylamine (3.19 mL), methanol (3 mL) and DMF (30 mL) was stirred at 80° C. for 15 hr under a carbon monoxide atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.53 g).
Reaction SMILES: [CH:1]([OH:3])=O.[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH:10]=[O:11])([O-:6])=[O:5].C(OC(=O)C)(=O)C>O>[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH:15][CH:1]=[O:3])[CH:10]=[O:11])([O-:6])=[O:5]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CNc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 79.7 %

Procedure:
To 56.6 ml (1.50 mol) of HCOOH was added 24.9 g (150 mmol) of 3-nitro-4-aminobenzaldehyde. The solution was heated to reflux, 28.4 ml (300 mmol) of acetic anhydride was added dropwise and the solution was refluxed for 30 minutes. The resulting suspension was cooled and poured into 400 ml of cold H2O with rapid stirring. The product was filtered, air dried, and recrystallized from isopropanol to yield 23.2 g (80%) of 3-nitro-4-formamidobenzaldehyde as a bright yellow powder: melting point=183°-191°.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C2C=CC=CC=2N=N1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[C:26]([CH2:27]O)=[C:25]([CH:29]([CH3:31])[CH3:30])[O:24][N:23]=1>ClCCl>[Cl:3][CH2:27][C:26]1[C:22]([C:16]2[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])=[N:23][O:24][C:25]=1[CH:29]([CH3:31])[CH3:30]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Yield: 102.8 %

Procedure:
Thionyl chloride (87 mL, 1.20 mol) was added dropwise to a stirred solution of benzotriazole (143 g, 1.20 mol) in dichloromethane (400 mL) at room temperature. The resulting solution was added dropwise during 30 min to a stirred solution of [3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (263 g, 0.92 mol) in dichloromethane (700 mL). A very mild exothermic reaction occurred with precipitation of benzotriazole hydrochloride. The mixture was filtered to remove the benzotriazole hydrochloride. The filtrate was washed with water (2×800 mL), 1N sodium hydroxide (800 mL) and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated to give 288 g of the product as a pale yellow oil. 1H NMR (DMSO-d6): 7.66 (m, 2H), 7.61-7.57 (m, 1H), 4.47 (s, 2H), 3.45 (septet, J=7 Hz, 1H), 1.31 (d, J=7 Hz, 6H). ESI-LCMS m/z 279 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.N1C=CC=CC=1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([NH:1][S:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:43])=[O:42])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(NS(=O)(=O)c3ccccc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
6-amino-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (30 mg, 0.079 mmol) was suspended in DCM (3 mL) followed by pyridine (0.032 mL, 0.395 mmol). The contents were vigorously stirred and then benzenesulfonyl chloride (0.011 mL, 0.087 mmol) was added and the contents stirred at RT for 1 h. The volatiles were removed in vacuo and dried on hi-vac for 1 h. The crude product was purified by reverse phase HPLC (Gradient B: 15-70%. A: Water+0.1% TFA. B: CH3CN+0.1% TFA). The product was neutralized with water and sat. NaHCO3, and extracted with 10% THF/EtOAC (hot) in duplicate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The solid was concentrated from DCM and dried in vacuum oven for 4 h at 45° C. The title compound was collected as 30 mg (72%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (td, J=5.49, 3.41 Hz, 2H), 1.75-1.94 (m, 4H), 1.99-2.10 (m, 2H), 2.12 (s, 3H), 2.20 (s, 3H), 4.30 (d, J=5.05 Hz, 2H), 4.89-5.04 (m, 1H), 5.89 (s, 1H), 7.22 (d, J=1.52 Hz, 1H), 7.36 (s, 1H), 7.48-7.63 (m, 3H), 7.77-7.84 (m, 2H), 8.11 (s, 1H), 8.36 (t, J=5.05 Hz, 1H), 10.56 (s, 1H), 11.55 (s, 1H); LC-MS (ES) m/z=519.2 [M+H]
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:15]2=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:23][C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:29])[N:16]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:17]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC(F)(F)F)c3cc(F)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1n(CC(F)(F)F)c2cc(F)ccc2n1C1CCNCC1
Reaction time: 9 h

Procedure:
A solution of 1-tert-butoxycarbonyl-4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine (4.17 g, 10 mmol.) in chloroform (50 mL) containing trifluoroacetic acid (5.5 mL) was stirred at room temp. under an inert atmosphere for 6-12 hours until reaction was complete. The solvent and excess TFA were removed and the residue redissolved in chloroform. This solution was washed with Na2CO3 /NaOH solution. The organic layer was dried (Na2SO4), filtered through a pad of charcoal, and the solvent evaporated to give 4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine as a viscous oil which was used as is. A sample of this material was converted to the HCl salt and after crystallization from methanol gave a white solid, mp: >280° C.
Reaction SMILES: [OH:1][C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:7][C:4]([CH3:5])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[O:1][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CNC(=O)C(C(O)=NO)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)C(C(=NO)OS(C)(=O)=O)C(C)(C)C
Temperature: 35 °C

Procedure:
A solution of 7.5 g (0.04 mol) of 1-hydroxy-3,3-dimethyl-2-methylcarbamyloximinobutane and 5.0 g (0.044 mol) of methanesulfonyl chloride in 50 ml of benzene is treated dropwise with 4.6 g (0.044 mol) of triethylamine with cooling to keep the temperature below 35° C. After the addition, the stirred mixture is heated at 35° C. for two hours and then washed with aqueous sodium bicarbonate and with water. The organic layer is dried over magnesium sulfate, filtered, stripped of volatiles to give 6.7 g (63%) of amber, viscous liquid residue, nD25 1.4810.
Reaction SMILES: B(Cl)(Cl)[Cl:2].C1[O:31][C:30]2[CH:29]=[CH:28][C:9]([CH2:10][NH:11][C:12]3[C:21]4[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=4)[N:15]=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:6]1.CO>C(Cl)Cl.C(Cl)(Cl)Cl>[ClH:2].[OH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2c(NCc3ccc4c(c3)OCO4)ncnc2c(OC)c1OC
Reactant: ClB(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(NCc3ccc(O)c(O)c3)ncnc2c(OC)c1OC
Product: Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
30 ml of a 1.0 M solution of boron trichloride in methylene chloride was dropped into a solution of 2.00 g (5.41 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline in 150 ml of chloroform under stirring at room temperature. The obtained mixture was stirred at room temperature for 2 days, followed by the addition of methanol and the obtained mixture was distilled under a reduced pressure to remove the solvent. This procedure was repeated thrice and the obtained residue was purified by silica gel column chromatography (chloroform/n-hexane). Hydrochloric acid/ethanol was added to the eluate and the obtained mixture was distilled under a reduced pressure to remove the solvent, followed by the addition of ethanol. The crystals thus formed were recovered by filtration. Thus, 0.59 g of the title compound was obtained as a colorless needle.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:41][NH2:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 8) (285 mg, 0.88 mmol) and N-methylmorpholine (110 μl, 1.00 mmol) in anhydrous tetrahydrofuran (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (130 μl, 1.00 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (130 μl, 1.06 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with aqueous citric acid solution (10% w/v, 10 ml) and stirred for 2 hours. This mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was then recrystallised from hexane: ethyl acetate to afford the title compound as a white solid (130 mg).
Reaction SMILES: [CH3:1][Al](C)C.[Si:5]([O:12][C@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:16]([CH:26]=O)[CH2:15][CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>C1COCC1.ICI.C(OCC)(=O)C.[Zn]>[Si:5]([O:12][C@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C@@H:16]([CH:26]=[CH2:1])[CH2:15][CH2:14]1)([C:8]([CH3:11])([CH3:9])[CH3:10])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1C=O
Reactant: C[Al](C)C
Agent: [Zn]
Solvent: ICI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of zinc dust (12.2 g) in THF (200 mL) and diiodomethane (5 mL) at 0° C. was added trimethylaluminium (2M in hexanes, 6 mL). After the addition the reaction was carefully warmed to room temperature (exothermic reaction!). The reaction was then cooled with an ice bath and a solution of tert-butyl (2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-formylpiperidine-1-carboxylate (Intermediate 189, 6.84 g) in THF (40 mL) was added. After 6 hours it was warmed to room temperature, the reaction was diluted with ethyl acetate and slowly quenched with a saturated aqueous solution of NaHCO3. The organic phase was collected and washed with NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Chromatography on silica gel with a gradient of 0-100% methylene chloride in hexanes gave 3.96 g of product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])(=O)=O.O>CN(C=O)C>[CH2:42]([N:43]([CH2:46][CH3:47])[CH2:44][CH2:45][O:26][C:22]1[CH:21]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:41]
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Reactant: CCN(CC)CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(diethylamino)ethyl methanesulfonate (30 mg, 0.15 mmol). The mixture was heated at 50° C. for 15 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated. The residue was purified by chromatography (silica, EtOAc) to give 6-(3-(2-(diethylamino)ethoxy)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (18 mg, 37%). 1H NMR (300 MHz, CDCl3): δ 8.64 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.59-7.53 (m, 3H), 7.45-7.36 (m, 2H), 7.28 (s, 1H), 7.04 (d, 1H, J=8.4 Hz), 6.23 (d, 1H, J=8.1 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.29-4.15 (m, 3H), 3.68 (brs, 1H), 3.52-3.49 (m, 1H), 2.97-2.93 (m, 2H), 2.72-2.65 (m, 4 h), 2.15-2.04 (m, 3H), 1.77 (brs, 3H), 1.26 (d, 3H, J=6.3 Hz), 1.11 (t, 6H, J=7.1 Hz). LC/MS: 486 [M+H]+, tR=1.48 min. HPLC: 95.50% at 214 nm, 96.62% at 254 nm, tR=5.45 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].CC([O-])(C)C.[K+].CS([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)(=O)=O.O>C1COCC1>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(C#N)cc2)nc1

Procedure:
To 3.04 g of 4-cyanophenol dissolved in a 15 ml THF/15 ml DMSO mixture was added 2.86 g of t-BuOK and then 6 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 60° C. for 11/2 hrs. After cooling, the reaction mixture was poured into water and the solid which formed collected. Recrystallization from acetonitrile gave purified 4-((5-(methylsulfonyl)-2-pyridinyl)oxy)benzonitrile, m.p. 195°-196° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:20]=[C:21]([C:24]([CH2:27]C(C)(C)C)([CH3:26])[CH3:25])[C:22]=1[OH:23])[CH2:12][P:13]1(=[O:19])[O:18]CC[CH2:15][O:14]1)([CH2:4]C(C)(C)C)([CH3:3])[CH3:2].[CH3:32][C:33](C)([CH2:36]O)[CH2:34]O.C(C1C=C(C=C(C(CC(C)(C)C)(C)C)C=1O)CP(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1)(CC(C)(C)C)(C)C.C(C1C=C(C=C(C(C)(C)C)C=1O)CP(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1)(C)(C)C>>[C:1]([C:9]1[CH:10]=[C:11]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[CH2:12][P:13]1(=[O:19])[O:18][CH2:32][C:33]([CH3:36])([CH3:34])[CH2:15][O:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CO)CO
Reactant: CC(C)(C)CC(C)(C)c1cc(CP2(=O)OCCCO2)cc(C(C)(C)CC(C)(C)C)c1O
Agent: CC(C)(C)CC(C)(C)c1cc(CP(=O)(Oc2ccccc2)Oc2ccccc2)cc(C(C)(C)CC(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CP(=O)(Oc2ccccc2)Oc2ccccc2)cc(C(C)(C)C)c1O
Product: CC1(C)COP(=O)(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC1

Procedure:
Similarly, 1-(3,5-di-tert-octyl-4-hydroxybenzyl)-1-oxo-2,6-dioxa-1-phosphacyclohexane is made by substituting 1,3-propanediol for 2,2-dimethyl-1,3-propanediol and diphenyl 3,5-di-tert-octyl-4-hydroxybenzylphosphonate for diphenyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate in the above example.