Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16]2)[C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.C1(C(N2CCN(CCO)CC2)C2C=CC([Cl:41])=CC=2)C=CC=CC=1.[K].CC([O-])(C)C.[K+].[Cl:58]CC([O-])=O.[Na+]>>[CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16]2)[C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.[ClH:41].[ClH:58]
Reactant: O=C([O-])CCl
Reactant: OCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: [K+]
Product: Cl

Procedure:
The process of UK-P No. 2 225 320 (Chem. Abstr., 113, 191395s) aims at the elimination of the disadvantages of the above known processes by preparing cetirizine from the {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol of the formula III which is converted to the potassium salt with potassium tert-butylate. The potassium salt is reacted with sodium chloro-acetate to obtain cetirizine dihydrochloride in a yield of 48.8%. In addition, 5.1% of a second generation product are obtained. Also an improved process is described for the preparation of the {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol of the formula III according to which 1-[(4-chlorophenyl)phenyl-methyl]piperazine of the formula VI is reacted with ethylene chlorohydrine in a yield of 90.4%, the total yield of the synthesis, referred to the piperazine derivative of the formula VI, is merely 48.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2C(=O)C3=CC=CC=C3C2=O)[N:5]=[C:4]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[CH:3]=1.NN.ClCCl>CO>[NH2:10][CH2:9][CH2:8][C:6]1[N:5]=[C:4]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(CCN2C(=O)c3ccccc3C2=O)nc(-n2c(C)ccc2C)c1
Agent: NN
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(CCN)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(2-phthalimidoethyl)pyridine (100 mg, 0.28 mmol) in 1.0 mL of methanol under nitrogen at room temperature was added hydrazine (0.018 mL, 0.56 mmol) via syringe. The mixture was stirred at room temperature overnight. Dichloromethane (2.0 mL) was added to the reaction. The precipitate was removed by filtration and washed with another 2 mL of dichloromethane. The combined filtrates were concentrated. The resulting residue was chromatographed on 7 g of silica gel, eluting with 100 mL of 5% methanol/dichloromethane followed by 200 mL of 96:4:1 dichloromethane/methanol/triethylamine to give 44 mg (68% yield) of 6-(2-aminoethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as colorless syrup.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1.N1C=CC=CC=1>C(Cl)Cl>[S:1]([O:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)([CH3:4])(=[O:3])=[O:2]
Reactant: CC(C)(C)OC(=O)C1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Mesyl chloride (0.15 ml) was added dropwise to tert-butyl 3-hydroxycyclopentanoate (373 mg) dissolved in methylene chloride (2 ml) and pyridine (0.32 ml) at a temperature of 0° C. The mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into ice-water (10 ml). The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to obtained the title compound having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([OH:16])[CH:8]=1)[CH3:2].[NH4+].[Cl-].CCO>[Fe].O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([OH:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc(N)c(O)c1

Procedure:
To a stirred suspension of 11-2 (4.64 g, 19.6 mmol), NH4Cl (524 mg, 9.8 mmol), EtOH (140 mL) and H2O (70 mL) was added iron dust (2.72 g, 48.9 mmol). The resulting yellow suspension was refluxed for 1.5 h., and then the solution was filtered while hot through celite. The filtrate was concentrated and the residue was partitioned between EtOAc and brine. The layers were separated and the EtOAc layer dried (Na2SO4) and concentrated to give 11-3 which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH:22]=O>>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1/[CH:22]=[C:7]1/[C:8](=[O:14])[C:9]2[C:5]([CH2:6]/1)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=Cc1ccncc1Br
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Br)C2

Procedure:
The title compound 89 is prepared according to the procedure reported in Example 34.1 with 5,6-dimethoxy-1-indanone (1.92 g, 10 mmol) and 3-bromo-4-pyridinecarboxaldehyde (2.3 g, 10 mmol) as reactants. White solid. (Yield 2.34 g, 65%).
Reaction SMILES: [CH3:1][CH:2]1[S:6](=[O:8])(=[O:7])[O:5][CH2:4][CH2:3]1.[OH-].[NH4+:10].CCO>O1CCCC1>[NH2:10][CH2:4][CH2:3][CH:2]([S:6]([OH:5])(=[O:8])=[O:7])[CH3:1]
Reactant: [NH4+]
Reactant: CC1CCOS1(=O)=O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CCN)S(=O)(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of 2,4-butanesultone (1.0 g, 7 mmol) in tetrahydrofuran (THF, 4.0 mL) was added via syringe pump over a 4 h period to ammonium hydroxide (28-30% NH3, 43 mL, 350 mmol) at 5° C. The solution was stirred at 5° C. for an additional 30 minutes. The solvent was coevaporated with EtOH (3×25 mL). The solid was dried in vacuo. Yield: 94%. 1H NMR (D2O, 500 MHz) δ ppm 3.05 (m, 2H), 2.90 (m, 1H), 2.05 (m, 1H), 2.06 (m, 1H), 1.77 (m, 1H), 1.18 (d, 3H, J=6.8 Hz), 1.14 (t, 3H, J=7.3 Hz). 13C (DMSO, 125 MHz) δ ppm 52.75, 38.20, 30.87, 17.27. ES-MS 154 (M+1).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[ClH:1].[Br:10][C:8]1[C:3]([F:2])=[CH:4][C:5]([NH2:9])=[N:6][CH:7]=1.[ClH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccn1
Agent: Cl
Solvent: CC#N
Product: Nc1cc(F)c(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To mono HCl salt of 4-fluoro-pyridin-2-ylamine (xviii) (3 g, 20.2 mmol) in acetonitrile at 0° C. was added in 3 portions N-bromosuccinimide (3.59 g, 20.2 mmol) over 1.5 h. The RM was stirred 1 h at 0° C. and the precipitate was filtered and dried under vacuo to give the title compound as mono HCl salt (tR 1.61 min (conditions 8), MH+=191, 193).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1>>[C:25]([CH2:24][C:20]1[CH:19]=[C:18]([NH:17][C:14]([C:12]2[O:13][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:10][CH:11]=2)=[O:16])[CH:23]=[CH:22][CH:21]=1)#[N:26]
Reactant: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1
Reactant: N#CCc1cccc(N)c1
Product: N#CCc1cccc(NC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (67) (62 mg, 0.24 mmol) was coupled to aniline (80) (32 mg, 0.24 mmol) using Method C. After work-up, the solid was recrystallised from MeCN (3 ml) to give the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:18]([OH:25])[C:19]#[C:20][Si](C)(C)C)[C:3]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C@@H:2]([C@@H:18]([OH:25])[C:19]#[CH:20])[C:3]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](O)C#C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#C[C@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 61.6 %

Procedure:
A solution of (4S)-N-[(2S,3R)-2-methyl-3-hydroxy-5-trimethylsilyl-4-pentynoyl]-4-benzyl-2-oxazolidinone (0.13 g) in 3 mL of dimethylformamide was treated with 48% aqueous HF (2.6 uL) and KF•2H2O at ambient temperature for 100 min. Upon completion of the reaction, saturated aqueous sodium bicarbonate was added to neutralize the HF, and the mixture was extracted three times with equal portions of ether. The organic extracts were combined, filtered, and dried over MgSO4. Filtration and evaporation gave the crude product, which was purified by silica gel chromatography (3:2 hexanes/ethyl acetate) to yield 64 mg of product.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:44])[CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:32][CH:31]=3)=[O:28])=[CH:21][C:20]=2[CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:26][N:25]1[C:19]2[CH:18]=[CH:17][C:16]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=3)=[CH:45][C:20]=2[CH:21]=[C:22]([C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][N:37]([CH3:44])[CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][CH:35]=2)=[O:28])[CH2:23][CH2:24]1
Reactant: CCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
In water: ethanol: toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-propoxyphenyl borate (203 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (455 mg). To the solution was added potassium carbonate (312 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (43 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate:ethanol:triethyleamine=100:5:1) and recrystallized from ethanol/hexane to give 1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (349 mg, 69%) as yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][N:18]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:17]2>>[CH:20]12[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]1)[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][NH:28][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=13)[CH2:19]2
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: NCCCN1CC2CCC(CC2)C1
Product: Cc1nnc(NCCCN2CC3CCC(CC3)C2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 3 equivalents of 3-(3-azabicyclo[3.2.2]non-3-yl)propylamine at 150° C. overnight gave the title compound as the free base which was purified by chromatography (silica gel, 1:4 methanol:methylene chloride containing ammonium hydroxide) and converted to the dihydrochloride salt (ethanol/etheral HCl), mp 343° C. dec.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[S:15]1[CH:19]=[C:18](B(O)O)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2>>[S:15]1[CH:19]=[C:18]([C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])=[C:2]([Cl:1])[N:10]=2)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Reactant: OB(O)c1csc2ccccc12
Product: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21

Procedure:
Following the procedure of Example 15d, 6-chloro-2-iodo-9-isopropyl-9H-purine (3.31 g, 0.0103 mol) was reacted with benzo[b]thiophen-3-ylboronic acid. The crude product was purified by silica gel chromatography (20 to 50% ethyl acetate in hexane) to afford the title compound as a solid. MS m/z 329.0 (M+1). 1H NMR (400 MHz, DMSO-d6): δ=9.15 (d, 1H), 8.85 (s, 2H), 8.17 (d, 1H), 7.62 (t, 1H), 7.53 (t, 1H), 5.06 (m, 1H), 1.71 (d, 6H).
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:39])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:18]([O:28][CH2:29][CH2:30][OH:31])=[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[CH3:47][O:46][C:44](=[O:45])[CH2:43][O:31][CH2:30][CH2:29][O:28][C:18]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:20][C:15]([C:14](=[O:39])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:16][C:17]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1
Reactant: COC(=O)CBr
Reactant: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(OCCOCC(=O)OC)c(-c2cccc(Cl)c2)c1
Temperature: 60 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of N-dodecyl-3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzamide (Example 1, Step 2), (0.866 g, 1.52 mmol) in THF (8 mL) was added NaH (0.10 g, 80%, 3.34 mmol). The mixture was stirred at 60° C. for 50 min and was then cooled to room temperature. Methyl bromoacetate (0.158 mL, 2.67 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction was cooled, quenched with 1.0 N HCl, and extracted with ethyl acetate. The organic phase was dried (MgSO4) and concentrated. Crude product was purified by HPLC. Yield: 0.177 g (18%) of product as an oil. 1H NMR (CDCl2) δ 7.72 (s, 2H), 7.63 (s, 2H), 7.50 (m, 2H), 7.39 (m, 4H), 6.20 (t, 1H), 3.78 (m, 5H), 3.49 (m, 4H), 3.31 (m, 2H), 1.68 (m, 2H), 1.30 (m, 18H), 0.88 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:24][CH:25]=[O:26])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Product: O=CC=Cc1ccc(Oc2ncccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyrimidinyloxy)benzaldehyde (prepared as described in Reference Example 9) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 227 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])=[N+:2]=[N-:3].[CH2:17]([OH:20])[C:18]#[CH:19]>C1(C)C=CC=CC=1>[OH:20][CH2:17][C:18]1[N:1]([CH2:4][CH2:5][N:6]2[C:7](=[O:16])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]2=[O:15])[N:2]=[N:3][CH:19]=1
Reactant: [N-]=[N+]=NCCN1C(=O)c2ccccc2C1=O
Reactant: C#CCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCn1nncc1CO
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Heat a mixture of 2-(2-azidoethyl)isoindoline-1,3-dione (12 g, 55.5 mmol) and 2-propyn-1-ol (3.88 mL, 66.6 mmol) in toluene (50 mL) in a sealed reactor at 90° C. for 3 days. Cool to RT and collect the solid. Purify by column chromatography (DCM to 2% methanol in DCM) to afford the title compound (first fraction) as a white solid (4.7 g, 31%). MS (EI) m/z 273 [M+1]+.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@@H:32]([N:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][C@@H:35]4[CH3:47])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.CCN(CC)CC.[CH3:73][S:74](Cl)(=[O:76])=[O:75]>C(Cl)Cl>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([C@@H:32]([N:34]3[CH2:39][CH2:38][N:37]([S:74]([CH3:73])(=[O:76])=[O:75])[CH2:36][C@@H:35]3[CH3:47])[CH3:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ncc(Nc2ncc([C@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A solution of (S)-tert-butyl 4-((S)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.101 g, 0.127 mmol) (the first-eluting diastereomer from Example 271, Step 4) in DCM (3.00 mL, 46.6 mmol) was treated with TFA (3.00 mL, 38.9 mmol) and the resulting mixture was stirred at room temperature for 30 min before being concentrated to give a brown oil. This oil was re-dissolved in DCM (3.00 mL) and sequentially treated with Et3N (0.089 mL, 0.636 mmol) and methanesulfonyl chloride (0.030 mL, 0.382 mmol) (slow addition) at −15° C., and the resulting mixture was stirred for 1 h. The reaction mixture was then quenched with saturated aqueous NaHCO3 and water. The separated aqueous layer was extracted with DCM (2×) and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was treated with TFA (2.00 mL) and heated at 80° C. overnight. The resulting mixture was allowed to cool to room temperature and was then concentrated in vacuo. The crude product was adsorbed onto silica gel and chromatographically purified (silica gel, 0% to 5% MeOH/DCM) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((S)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (29 mg, 0.055 mmol, 42.9% yield) as a yellow solid. m/z (ESI, +ve ion) 532 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H); 8.74 (d, J=2.54 Hz, 1H); 8.27-8.46 (m, 3H); 7.90 (br. s., 1H); 7.77 (br. s., 1H); 3.99-4.09 (m, 1H); 3.93 (s, 3H); 3.20-3.30 (m, 1H); 2.94-3.11 (m, 2H); 2.84 (s, 3H); 2.75-2.84 (m, 2H); 2.45 (s, 3H); 2.40 (dd, 1H); 2.29-2.35 (m, 1H); 1.28 (d, J=6.65 Hz, 3H); 1.15 (d, J=6.26 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:17]C1CCCCO1)/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@@H:10]([OH:17])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/[C@H](OC1CCCCO1)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 75 %

Procedure:
Using the procedure of Example 6 with the resultant compound of Example 12 provided, following silica gel chromatography using a gradient of 15-30% ethyl acetate in hexane, the desired compound (m.p. 108°-109° C., Rf 0.44, 2:1 hexane:ethyl acetate) in 75% yield. 1H NMR (CDCl3) 1.39 (s, 9 H), 2.96 (d, J=8 Hz, 2 H), 3.73 (s, 3 H), 3.75-3.85 (m, 2 H), 4.32 (br, 1 H), 4.79 (br d, 1 H), 6.11 (br d, J=15 Hz, 1 H), 6.94 (dd, J=15, 4 Hz, 1 H), 7.2-7.35 (m, 5 H). Mass spectrum: (M+H)+ =336.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].[CH2:26]([O:31][CH:32]([CH3:49])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:27][CH2:28][CH2:29][CH3:30].Cl>O.CN(C)C=O>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([O:31][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:49])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCOC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCCCCC)cc2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
Separately, 3.12 g of 5-n-decyl-2-(4-hydroxyphenyl)pyrimidine and 0.53 g of potassium hydroxide were added to 14 ml of dimethylformamide, and the mixture was stirred for 3 hours at 100° C. To the mixture was added the above-prepared 2.98 g of 6-pentyloxyheptyl-p-toluenesulfonate followed by 5 hours of stirring under heating at 100° C. After the reaction, the reaction mixture was poured into 200 ml of cold water and acidified to about pH 3 with 6N-hydrochloric acid and extracted with benzene, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent, to obtain 4.71 g of crude product. The product was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/2) and recrystallized from hexane to obtain 1.56 g of 5-n-decyl-2-[4-(6-pentyloxyheptyloxy)phenyl]pyrimidine.
Reaction SMILES: [CH:1]([O:3][N:4]=[C:5]([C:11]1([O:16][CH2:15][CH2:14][O:13]1)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[CH:17]([Br:20])(Br)[Br:18].C(O)C.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[Br:18][C:17]1([Br:20])[CH2:2][CH:1]1[O:3][N:4]=[C:5]([C:11]1([O:13][CH2:14][CH2:15][O:16]1)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: BrC(Br)Br
Reactant: C=CON=C(C(=O)OCC)C1(C)OCCO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(=NOC1CC1(Br)Br)C1(C)OCCO1
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-vinyloxyimino-3,3-ethylenedioxybutyrate (syn isomer)(15 g) and benzyl-triethylammonium chloride (164 mg) in a mixture of methylene chloride (13 ml), bromoform (11.4 ml) and ethanol (0.65 ml) was added 50% aqueous solution of sodium hydroxide (105 ml) under ice-cooling. The mixture was stirred for 1 hour at the same temperature and allowed to be stirred at ambient temperature overnight. The mixture was extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using a mixture of chloroform and ethyl acetate (4:1 V/V) as an eluent to give ethyl 2-(2,2-dibromocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(15.4 g) as an oil.