Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]=[C:14]=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N[CH2:17][C:18]1[CH:19]=[C:20]([Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[O:21][CH:22]=1.C([N:32](CC)CC)C>O1CCCC1>[CH2:1]([N:13]([CH2:17][C:18]1[CH:19]=[C:20]([Si:23]([CH2:24][CH3:25])([CH2:28][CH3:29])[CH2:26][CH3:27])[O:21][CH:22]=1)[C:14]([NH2:32])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC[Si](CC)(CC)c1cc(CN)co1
Reactant: CCCCCCCCCCCCN=C=O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(Cc1coc([Si](CC)(CC)CC)c1)C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dodecylisocyanate (105 mg, 0.49 mmol) was added to a solution of 4-aminomethyl-2-triethylsilylfuran (Compound 2, 70 mg, 0.33 mmol) and triethylamine (69 microliter, 0.49 mmol) in tetrahydrofuran (3 ml) at room temperature. After stirring at room temperature overnight (ca. 16 hours), the reaction mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave a residue which was purified by flash chromatography on silica using 60% ethyl ether/hexane. Fractions of Rf of about 0.47 on evaporation gave the title urea as an off-white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]([CH3:25])([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])[CH3:14])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]([CH3:25])([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)=[O:17])[CH3:14])#[N:12]
Reactant: CC(C)(C#N)OC(=O)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)OC(=O)N1CCC(=O)CC1
Reaction time: 1 h
Yield: 78 %

Procedure:
5.06 ml of dimethylsulfoxide was gradually dropped, at -78° C. into a solution of 4.15 ml of oxalyl chloride in dichloromethane (50 ml), into which a dichlorometane solution of 5.05 g of 1-(1-cyano-1-methylethoxycarbonyl)-4-hyroxypiperidine was dropped. After agitation at the temperature for 1 hour, 16.57 ml of triethylamine was added, followed by agitation at room temperature for 1 hour. The reaction solution was filtered, washed with water, and dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant residue was purified by silica gel column chromatography (elution solvent: ethyl acetate:n-hexane=1.9), thereby obtaining 3.9 g of the intended compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[S:17][C:16]([NH2:18])=[N:15][C:14]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[S:17][C:16]([NH:18][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[N:15][C:14]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(NC3CCCC3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)Nc3ccccc3)sc2-c2ccnc(NC3CCCC3)c2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of [5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.43 g, 1.2 mmol) in N,N-dimethylacetamide (10 mL) was added phenyl isocyanate (0.19 mL, 1.8 mmol) and the mixture was stirred at 80° C. for 1 hr. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1). The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (0.23 g, yield 39%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(F)cc1
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: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1ccc(-c2ccc(F)cc2)nc1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A mixture of 6-chloronicotinamide (5.00 g, 31.95 mmol), 4-fluorobenzene boronic acid (4.92 g, 35.14 mmol), and Pd(PPh3)4(1.10 g, 0.96 mmol) in a mixture of toluene (80 ml), ethanol (12 ml) and 2M sodium carbonate (36.74 ml, 73.48 mmol) was degassed (N2) and heated at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and then filtered. The collected solid was washed with water and dried. The dried solid was taken up in methanol (100 ml) and heated to reflux for 20 minutes. The mixture was then cooled to room temperature, filtered and the solid dried to give the title compound (6.25 g, 90%) as a pale grey solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](=O)[CH3:5].[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:5][CH:4]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:20][CH:19]=1)[CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: CC(=O)CC(C)C
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(C)CC(C)Nc1ccc(Nc2ccccc2)cc1

Procedure:
A mixture of 500g. (5 moles) 4-methyl-2-pentanone and 184 g. (1 mole) N-phenyl-p-phenylenediamine containing 10 g. copper chromite catalyst was reacted at 150°-160° C and 1000 psi hydrogen pressure until the hydrogen uptake became very slow. After filtering off the catalyst and topping off the filtrate at 100 mm. and 100° C, 208 g. still pot residue of crude product N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine was obtained, while the excess 4-methyl-2-pentanone, and the water and 4-methyl-2-pentanol byproducts were stripped off; no attempt was made to isolate the Schiff's base III [R1 =C6H5, R2 =CH3, R3 =--CH2CH(CH3)2 ]. The antiozonant product N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (IV) [R1 =C6H5, R2 =CH3, R3 =CH2CH(CH3)2 ] was soft and mushy, melting at 43°-50° C; when a sample of this product was kept at 46°-47° C. for one hour, most of the sample liquefied, and when held for 23 hours at 40°-42° C. or for 3.3 hours at 44°-45° C, much of it melted.
Reaction SMILES: [CH2:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH:4][CH3:5])[CH3:2].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH2:4]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH:7]=1)[CH:21]=[O:22])=[CH:1][CH3:2])[CH3:5]
Reactant: CN(C)C=O
Reactant: CC=C(CC)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC=C(CC)c1ccc(F)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
A solution of 1-(1-ethyl-propenyl)-4-fluoro-benzene (15.3 g, 93.2 mmol) in THF (150 mL) at −78° C. is treated with n-BuLi (70 mL, 1.6 M). The reaction mixture is allowed to warm to 0° C. over 60 min, cooled to −78° C., and treated with DMF (10.2 g, 140 mmol). The mixture is stirred for 10 min and quenched with HOAc (10 mL) and water (200 mL). The mixture is allowed to warm to RT, and the THF is removed under vacuum. The residue is extracted with EtOAc (2×100 mL, and the organic layer is dried over Na2SO4 and concentrated. The crude product is purified using silica gel column chromatography (7% EtOAc/Hex) to afford the title compound (8.70 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[C:20]5[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=4[S:19][CH2:18]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=5)[CH2:13][CH2:14]2)=[CH:27][CH:26]=1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)COc4ccc(Cl)cc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 210 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=109-110° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.21 (brs, 1H), 7.10 (dd, 1H), 6.97 (d, J=9.2 Hz, 2H), 4.84 (s, 1H), 3.98 (brm, 6H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H), 1.99 (m, 2H), 1.82 (m, 2H); LCMS: 516 [M+H].
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH3:23]>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH3:23])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: CBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Solvent: CC#N
Product: C[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 65.7 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (30.0 mg, 0.107 mmol) and bromomethane (0.09 mL, 0.18 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (26.3 mg, 65%). EI-MS m/z 294 (M+) Rt (1.30 min).
Reaction SMILES: Cl[B:2]1[NH:7][B:6](Cl)[NH:5][B:4](Cl)[NH:3]1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([N:19]([CH2:22][CH3:23])CC)C>C1(C)C=CC=CC=1>[CH2:10]([NH:16][B:2]1[NH:7][B:6]([NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH:5][B:4]([NH:19][CH2:22][CH2:23][CH2:10][CH2:11][CH2:12][CH3:13])[NH:3]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: CCN(CC)CC
Reactant: ClB1NB(Cl)NB(Cl)N1
Solvent: Cc1ccccc1
Product: CCCCCCNB1NB(NCCCCCC)NB(NCCCCCC)N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
B,B′,B″-trichloroborazine (15 g) was dissolved into sufficiently dewatered toluene (100 mL) and a mixture solution of n-hexyl amine (37 g), triethyl amine (25 g) and toluene (100 mL) was dropped over 1 hour at room temperature. After completion of the drop-wise addition, the solution was stirred at 25° C. for 3 hours and further at 60° C. for 3 hours. An amine-HCl salt generated was removed by filtration, followed by removal of the solvent and unreacting amine under reduced pressure to obtain B,B′,B″-tris(hexylamino)borazine as yellow viscous liquid (30 g). Thus obtained compound was further stirred in xylene at 130° C. for 3 hours to proceed polycondensation reaction. After the reaction, the solvent is removed under reduced pressure to obtain a borazine ring-containing compound 2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(F)cc2F)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15].N1([C:22]2[CH2:27][CH2:26]C[CH2:24][CH:23]=2)CCCC1>O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:26]2[CH2:27][CH2:22][CH2:23][CH2:24][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)CC2CCCCC2=O)cc1

Procedure:
A solution of 50 g. (0.23 mole) of p-methylphenacyl bromide in 120 ml. of dry dimethyl formamide was added dropwise during 1/2 hour into a stirred, cooled solution of 35.4 g. (0.23 mole) of 1-pyrrolidino-1-cyclohexene in 200 ml. of dimethyl formamide at a rate to maintain a temperature of 25°. After 51/2 hours, the solution was diluted with water and extracted with chloroform. The chloroform solution was washed with water, dried over sodium sulfate and concentrated to an oil. Distillation gave 28.5 g. (53%) of liquid, b.p. 161°-165° (0.2 mm.), which solidifed (m.p. 65°-70°).
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[CH3:10])#N.[OH2:17].[OH-].[Na+].[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:2]([CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[CH3:10])=[O:17])[CH3:21]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CC#N
Reactant: CCO
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1nc(-c2ccccc2)[nH]c1C

Procedure:
Hydrochloric acid in ethanol (35%, 150 ml) was added to 4-cyanomethyl-5-methyl-2-phenylimidazole (20.5 g) and heated to reflux temperature. After 1 h the reaction mixture was poured into water (400 ml) and NaOH was added (pH>8), followed by extraction with dichloromethane (3 times). The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])[CH:18]=[CH:17]3.[CH3:32][Cu]C.[Li].[Cl-].[NH4+].C1C=CC=CC=1>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])[CH2:18][C@H:17]3[CH3:32]
Reactant: C[C@H]1CC(=O)C=C2C=C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17β,19-dihydroxy-1α-methyl-4,6-androstadien-3-one diacetate in anhydrous tetrahydrofuran is added slowly to an ice cold ethereal solution of lithium dimethylcopper prepared as in the preceding Example. Stirring is continued for 30 minutes and the mixture is poured onto a saturated aqueous ammonium chloride solution. Benzene is added and the mixture filtered through diatomaceous earth. The organic layer is washed with aqueous ammonium chloride, water, dried over magnesium sulfate and evaporated to dryness. The residue is stirred at room temperature with aqueous methanolic hydrochloric acid for 1 hour and poured onto ice water. The gum which forms is extracted with ether, washed with water, dried over magnesium sulfate and the ether removed. The residue is chromatographed on silica gel and eluted with benzene. The eluate is recrystallized from hexane to give 17β,19-dihydroxy-1α,7α-dimethyl-4-androsten-3-one diacetate.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([NH:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH:45](O)[CH2:44]3)=[N:9]2)=CC=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>>[F:55][C:54]([F:57])([F:56])[C:52]([O:58][CH:45]1[CH2:46][CH2:47][CH2:48][CH:43]([NH:42][C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[CH2:44]1)=[O:53]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCCC(OC(=O)C(F)(F)F)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 78 %

Procedure:
A solution of N-(4-(1-(4-methoxybenzyl)-3-(3-hydroxycyclohexylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (40 mg, 0.058 mmol) in TFA (1 mL) was heated to 50° C. for 1 hour. Excess TFA was evaporated and the residue was dissolved in EtOAc. The organic layer was then washed with saturated aqueous NaHCO3, brine, dried with Na2SO4, filtered and concentrated to afford the product (30 mg, 78% yield) as a yellow solid. LRMS (APCI pos) m/e 670.2 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ 12.20 (d, 1H), 11.70 (s, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 8.12 (dd, 1H), 8.02 (dd, 1H), 7.66-7.70 (m, 2H), 7.56-7.62 (m, 1H), 7.46-7.52 (m, 1H), 7.38-7.44 (m, 2H), 6.02 (d, 2H), 5.20-5.40 (m, 1H), 3.60-3.80 (m, 1H), 2.20-2.30 (m, 1H), 2.00-2.10 (m, 2H), 1.80-1.90 (m, 2H), 1.60-1.80 (m, 2H), 1.30-1.45 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:14](O)[CH2:15][CH2:16][OH:17].[OH-:19].[Na+]>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:19][CH:16]([OH:17])[CH2:15][CH3:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: OCCCO
Reactant: [OH-]
Agent: [Na+]
Product: CCC(O)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a mixture of 0.2 mol (40.5 g) of 2,4-dinitro chlorobenzene and of 1.12 mol (81 cm3) of 1,3-propanediol, heated to 90° C. is added in 30 minutes 1.1 mol (81 cm3) of 1,3-propanediol in 20 cm3 of 10 N sodium hydroxide.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[CH3:19][O:20][CH2:21][N:22]=[C:23]=[O:24]>>[CH3:19][O:20][CH2:21][NH:22][C:23]([NH:1][CH:2]1[CH2:3][C:4]([CH3:18])([CH3:17])[N:5]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([CH3:8])([CH3:9])[CH2:7]1)=[O:24]
Reactant: COCN=C=O
Reactant: CC1(C)CC(N)CC(C)(C)N1Cc1ccccc1
Product: COCNC(=O)NC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1

Procedure:
51 parts of N-methoxymethyl-N'-1-benzyl-2,2,6,6-tetramethylpiperidin-4-yl urea were obtained by reacting 49.1 parts of 4-amino-1-benzyl-2,2,6,6-tetramethylpiperidine with methoxymethyl isocyanate in the same way as described in Example 23(b).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:16][C:15]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14]1.[NH4+].[Cl-]>C(Cl)Cl>[CH:12]([CH:13]1[CH2:14][C:15]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16]1)=[O:11]
Reactant: CCOC(=O)C1(C)CC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C1(C)CC(C=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a solution of oxalyl chloride (0.549 mL, 6.27 mmol) in DCM (15 mL) was added DMSO (0.890 mL, 12.54 mmol) as a solution in DCM (5 mL) slowly at −78° C. The resultant solution was stirred for 30 min prior to dropwise addition of Intermediate 258B (0.5 g, 3.14 mmol) as solution in DCM (5 mL). The resultant mixture was stirred for an additional 2 h at −78° C. TEA (4.37 mL, 31.4 mmol) was added to the reaction and the reaction mixture was allowed to stir at −78° C. for 30 min. The mixture was then warmed to RT and a saturated aqueous NH4Cl solution was added and extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 258C as a pale yellow liquid (0.12 g, 22%, mixture of cis and trans isomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.63 (d, J=1.51 Hz, 1H), 3.95-4.15 (m, 2H), 3.08-3.28 (m, 1H), 2.53-2.61 (m, 2H), 2.16-2.28 (m, 1H), 1.93-2.14 (m, 2H), 1.37-1.43 (s, 1H), 1.21-1.30 (s, 2H), 1.13-1.21 (m, 3H).
Reaction SMILES: C(OC([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[O:21][CH3:22])=O)C.C(Cl)(Cl)Cl.[Br:27]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:8]2[C:7]([O:21][CH3:22])=[C:6]([Br:27])[S:20][C:9]=2[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1sc2c(c1OC)CCN(C(=O)OCC)CC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCc2sc(Br)c(OC)c2CC1

Procedure:
The product of step c) (17 mg, 0.067 mmol) was dissolved in 1 mL 1:1 acetic acid:CHCl3 and treated with N-bromosuccinimide (12 mg, 0.068 mmol). After 30. minutes, the reaction solution was added dropwise to a solution of saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts were concentrated to give the subtitle compound, which was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([P:24](=[O:33])([O:29][CH:30]([CH3:32])[CH3:31])[O:25][CH:26]([CH3:28])[CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:34](=[O:36])=[O:35]>CCOCC.C1COCC1>[CH:30]([O:29][P:24]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:34]([OH:36])=[O:35])([O:25][CH:26]([CH3:28])[CH3:27])=[O:33])([CH3:32])[CH3:31]
Reactant: O=C=O
Reactant: CCCCCCCCCCCP(=O)(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCC(C(=O)O)P(=O)(OC(C)C)OC(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
196 g (1.94 moles) of diisopropylamine was added to a flame-dried, 5 liter flask fitted with mechanical stirrer, condenser, thermometer and addition funnel. The flask was cooled to 0°-10° C. using a dry ice/acetone bath. 808 ml of n-butyllithium (2.4M, 1.95 moles) was slowly added, while the flask was kept at 0°-10° C. The solution was stirred for an additional 15 minutes and then chilled to -78° C. 598 g (1.84 moles) of diisopropyl undecylphosphonate was added in 1000 ml of freshly distilled THF. (The addition rate should be slow enough to maintain the temperature below -60° C.) The mixture was stirred for an additional 2 hours and then poured carefully into a 12 liter flask containing about 2 kg of dry ice in 3.78 liters of ether. This mixture was allowed to stand and warm slowly overnight. The solution was extracted with water to collect the lithium salt of the product. The organic layers contained any unreacted diisopropyl undecylphosphonate. The water layer was acidified to pH 2.0 using concentrated HCl and extracted with 500 ml of ether three times. The combined ether extracts were dried over magnesium sulfate, filtered, and flash evaporated. The product was a viscous oil weighing 553 g (81% yield) and was sufficiently pure (by 1H NMR) for use in the next step.