Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:19][NH2:20].CO>C(O)C>[NH:19]([C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:20]
Reactant: NN
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Solvent: CCO
Solvent: CO
Solvent: O
Product: NNc1cc(-c2ccccc2)c2ccccc2n1

Procedure:
In carrying out the process of the present invention, a 2-chloro-4-phenylquinoline I is heated with hydrazine hydrate. In the preferred embodiment of this invention, the reaction is carried out at the reflux temperature of the mixture; however, temperatures between 25° and 118° C. with a reaction time of 1 to 18 hours are operative. A solvent, such as lower alkanol, e.g., methanol, ethanol, 1- and 2-propanol can be used but is not necessary. In the preferred embodiment of the invention, one hour reflux under nitrogen is sufficient. At the termination of the reaction, the mixture is concentrated, poured into water and the insoluble product collected on a filter. Purification is carried out by conventional means such as extraction, chromatography or more commonly recrystallization to obtain the corresponding 2-hydrazino-4-phenylquinoline II.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH:9](O)[C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2].C(N(S(F)(F)[F:31])CC)C>ClCCl>[CH2:1]([N:3]1[C:8]([CH:9]([F:31])[C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCn1c(C(O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Solvent: ClCCl
Product: CCn1c(C(F)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a solution of 3-[(3-Ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-hydroxy-methyl]-5-methyl-benzonitrile (100) (55.7 mg, 0.17 mmol) in dichloromethane (2.0 mL) at 0° C. was added (diethylamino)sulfur trifluoride (33 μL, 0.255 mmol) and reaction mixture stirred for 1 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (2×). The combined organic layer was dried (MgSO4), concentrated and purified by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give a white powder after lyophilization (45 mg, 80%). 1H NMR (300 MHz, CD3OD): 7.60 (s, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.04 (d, J=45.9 Hz, 1H), 3.75-3.57 (m, 2H), 2.94-2.89 (m, 1H), 2.40 (s, 3H), 1.24 (d, J=6.9 Hz, 3H), 1.1-1.0 (s, 6H); %). 19F NMR (CD3OD): −180.5; Mass Spectrum: 330.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][C:33](Cl)=[O:34]>O.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH:11][C:33](=[O:34])[CH2:32][Br:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CBr)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
To an ice-cooled solution of (1R)-N1 -(tert-butoxycarbonyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (7.00 g) in a mixed solvent of dichloromethane (200 ml) and dimethylformamide (200 ml) was added potassium carbonate (10.03 g). To the mixture was added dropwise bromoacetyl chloride (7.61 g) for 3 minutes, and then the mixture was stirred at the same temperature for 1 hour and 40 minutes by adding further potassium carbonate (3.34 g) and bromoacetyl chloride (2.00 ml) into the mixture. The resulting mixture was poured into water, and extracted twice with dichloromethane. The extracts were combined and washed successively with 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was dried to give (1R)-N1 -(tert-butoxycarbonyl)-N2 -(bromoacetyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (9.9 g) as crystal.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccncc1
Product: N#Cc1cc(-c2ccncc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (64 mg, 89%), MS (ISP) m/z=289.5 [(M+H)+], mp 315.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15][N:16](C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20]N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:20][N:16]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 mL, 1.25 equiv). The solution was heated to reflux, immediately allowed to cool to room temperature, and concentrated to give 1.4 g (63%) which was used without purification. Mass spec.: 224.11 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]([CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)[CH3:6])=[O:4].Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Cl.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[OH:1][CH2:2][C:3]([N:5]([CH3:6])[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)=[O:4]
Reactant: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1O
Reactant: ClCc1ccccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.6 %

Procedure:
2-Hydroxy-N-[2-({4-[4-hydroxy-3-methylanilino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (100 mg), picolyl chloride hydrochloride (60 mg) and potassium carbonate (120 mg) were stirred in DMF (5 ml) to which was added 18-crown-6 (10 mg). The reaction was stirred at room temperature for 2 days. The DMF was removed in vacuo, water (5 ml) was added and then the suspension was extracted with DCM (2×5 ml). The DCM fraction was purified by chromatography using 2.5-5% of 10:1 DCM/methanol containing 0.5% ammonia (0.880) as eluent. The appropriate fractions were evaporated, and the residue was precipitated from DCM/diethyl ether to give the title product as a light yellow solid (28 mg, 23%); NMR spectrum (DMSO-d6, 100° C.) 2.29 (s, 3H), 3.00 (s, 3H), 3.90 (t, 2H), 4.16 (s, 2H), 4.50 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.16 (d, 1H), 7.34 (d, 2H), 7.51 (m, 2H), 7.55 (d, 1H), 7.79 (t, 1H), 7.83 (td, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.62 (s, 1H); Mass spectrum MH+ 474.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH:14]([OH:30])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].C(=O)([O-])[O-].[K+].[K+].[C:40]([CH2:42][C:43]([NH2:45])=[O:44])#[N:41]>C(#N)C.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:40]([C:42]1[C:43](=[O:44])[NH:45][C:5]([CH3:6])=[C:4]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH:14]([OH:30])[CH2:15][N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:20][CH2:21]3)=[CH:10][CH:9]=2)[CH:3]=1)#[N:41]
Reactant: COc1ccccc1N1CCN(CC(O)COc2ccc(C(=CN(C)C)C(C)=O)cc2)CC1
Reactant: N#CCC(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CC(O)COc2ccc(-c3cc(C#N)c(=O)[nH]c3C)cc2)CC1
Yield: 23.4 %

Procedure:
9.0 g of 1-[4-(4-dimethylamino-3-buten-2-on-3-yl)-phenoxy]-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan2-ol are heated under reflux in 100 ml of acetonitrile with 5.66 g of potassium carbonate, 0.67 g of tetrabutylammonium bisulphate and 2.52 g of cyanoacetamide for 36 hours. The solvent is then distilled off in vacuo, the residue is dissolved in 50 ml of water and the solution is neutralised with dilute hydrochloric acid and extracted several times with ethyl acetate. The extracts are dried and concentrated. The residue is purified by column chromatography on silica gel (chloroform:methanol=10:1). 2.2 g of 1-[4-(3-cyano-1,2-dihydro-6-methyl-2-oxo-pyridin-5-yl)-penoxy]-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-2-ol are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:27][C:28]1[N:33]=[C:32](I)[C:31]([OH:35])=[CH:30][CH:29]=1>O1CCOCC1.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]>[Cl:27][C:28]1[N:33]=[C:32]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]3[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=2)[C:31]([OH:35])=[CH:30][CH:29]=1
Reactant: COc1ccc2c(cc(B(O)O)n2C(=O)OC(C)(C)C)n1
Reactant: Oc1ccc(Cl)nc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1ccc2c(cc(-c3nc(Cl)ccc3O)n2C(=O)OC(C)(C)C)n1
Temperature: 70 °C
Yield: 59.1 %

Procedure:
To a degassed solution of (1-(tert-butoxycarbonyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)boronic acid (500 mg, 1.17 mmol), NaHCO3 (287 mg, 3.42 mmol) and 6-chloro-2-iodopyridin-3-ol (525 mg, 2.05 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (10 mg) under N2. The mixture was heated at 70° C. for 5 hours, concentrated in vacuo to remove 1,4-dioxane and extracted with EtOAc. After washed with brine and dried over Na2SO4, the solvent was removed by distillation. After concentrated, the crude product of tert-butyl 2-(6-chloro-3-hydroxypyridin-2-yl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (260 mg, yield: 40%). MS (M+H)+: 376/378.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([O:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O[C:36](=[O:38])[CH3:37])(=O)C>C(Cl)(Cl)Cl>[C:22]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:26]([O:29][C:36](=[O:38])[CH3:37])[CH2:27][O:28][C:25](=[O:24])[CH3:26])=[O:23])=[CH:30][CH:31]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)OCC(COC(C)=O)OC(C)=O)cc1

Procedure:
A solution of 6.53 g of 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate in 100 ml of chloroform is stirred under reflux while 9.0 ml of acetic anhydride is added and for 6 hours thereafter. The solution is extracted with 2% aqueous sodium carbonate solution and water, dried, and evaporated to yield 2,3-diacetoxypropyl N-acetyl-4-(n-hexadecylamino)benzoate as a yellow oil.
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=O.Cl.NC1[N:19]=[CH:20][NH:21][C:22]=1[C:23]([NH2:25])=[O:24].C(#N)C.C(O)C>C(O)(=O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]2[N:19]3[CH:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:15]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cccc(-c2ccnc3c(C(N)=O)ncn23)c1

Procedure:
A stirred mixture of 15.0 g of 3-dimethylamino-3'-methoxyacrylophenone (prepared as described in Example 5and 9.2 g of 4-amino-5-imidazolecarboxamide hydrochloride in 150 ml of glacial acetic acid was heated at reflux for 24 hours. The solvent was evaporated in vacuo and the crystalline residue was treated with 100 ml of saturated sodium bicarbonate solution, filtered and washed with 200 ml of water to give yellow crystals. This material was treated with 400 ml of acetonitrile then with 600 ml of hot ethanol to give 9.9 g of the product of the example as yellow crystals, mp 249°-252° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.CS(O[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1)(=O)=O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: CS(=O)(=O)Nc1cccc(CCOS(C)(=O)=O)c1
Reactant: Cc1ncc2c(N3CCNCC3)cccc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc2c(N3CCN(CCc4cccc(NS(C)(=O)=O)c4)CC3)cccc2n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
A mixture of 2-methyl-5-(1-piperazinyl)quinazoline (50 mg), 2-{3-[(methylsulfonyl)amino]phenyl}ethyl methanesulfonate (65 mg), diisopropylethylamine (192 μL) and DMF (0.5 mL) was heated to 100° C. in a sealed tube and stirred for 24 hours. The mixture was cooled to room temperature and partitioned between aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed (water, brine), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; DCM-MeOH: (100:0)→(95:5)] to give the title compound as a beige foam (35 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([CH3:16])=[C:10]2[C:5]=1[CH2:6][CH2:7][C@@:8]([CH3:33])([CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[O:9]2)[CH:2]=[CH2:3].C(#N)C.[O:37]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>O.CC(OC)(C)C.C(Cl)Cl>[CH2:1]([C:4]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:9])[C:5]=1[CH2:6][CH2:7][C@@:8]([OH:37])([CH3:33])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(C)c(C)c2c1CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
A 50 mL RBF flask was charged with (R,R,R)-5-allyl-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol (Ex-1D-3) (120 mg, 0.26 mmol) and ACN (20 mL), then cooled to 0° C. A solution of CAN (285 mg, 0.52 mmol) in water (1 mL) was added dropwise over 1 min to the reaction resulting in a bright orange solution. After 15 min, the reaction was deemed complete (TLC—9:1 hept:EtOAc). The reaction was diluted with MTBE (10 mL) and water (10 mL). The aqueous layer was washed with MTBE (3×10 mL). The combined, MTBE layers were washed with brine (5 mL), dried over MgSO4, filtered and concentrated by rotary evaporation to yield an orange oil. The oil was dissolved in DCM (10 mL) and passed through a silica plug. The DCM eluent was concentrated by rotary evaporation to yield (R,R,R)-2-allyl-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5,6-dimethyl-[1,4]benzoquinone (Ex-1D-4) as an orange oil (100 mg, 80%). 1H NMR (400 MHz, CDCl3) δ (ppm): 5.83 (ddt, 1H), 5.10-5.05 (m, 2H), 3.29 (d, J=6.2 Hz, 2H), 2.59-2.45 (m, 2H), 2.04 (s, 6H), 1.56-1.00 (m, 24H), 1.25 (s, 3H), 0.89-0.85 (m, 12H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:3].[C:23]([NH:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:40]([C:44]([NH:46][CH:47]([CH:56]([OH:68])[CH2:57][O:58][CH2:59][C:60]3[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:67])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:45])[CH2:41][CH2:42][CH2:43][N:36]2[C:35](=[O:69])[CH2:34][CH2:33]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CCOC(C)=O>[C:23]([NH:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:40]([C:44]([NH:46][CH:47]([C:56](=[O:68])[CH2:57][O:58][C:59](=[O:3])[C:60]3[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:67])[CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])=[O:45])[CH2:41][CH2:42][CH2:43][N:36]2[C:35](=[O:69])[CH2:34][CH2:33]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(O)COCc1c(Cl)cccc1Cl
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COC(=O)c1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 69.5 %

Procedure:
Dess-Martin reagent (3.82 g; 9.0 mmol) was added to a stirred solution of the alcohol 215e (3.17 g; 4.5 mmol) in CH2Cl2 (100 ml). The mixture was sirred for 1 h, diluted with EtOAc (300 ml), then washed with a 1:1 mixture of sat. Na2S2O3 and sat. NaHCO3 (100 ml) followed by brine (100 ml). The mixture was dried (MgSO4) then concentrated. The residue was purified by flash chromatography to afford 2.2 g (70%) of 216e as a colourless solid: mp 102-107° C.; [α]D32 −82.5 (c 0.1, CH2Cl2); IR (KBr) 3374, 2937, 1739, 1661, 1525, 1433, 1275, 1260, 1152; 1H NMR (CDCl3) δ7.85-7.78 (2H, m), 7.57-7.32 (6H, m), 7.09 (1H, d, J=7.9), 7.01 (1H, d, J 7.3), 5.25-5.16 (1H, m), 5.16-5.05 (1H, m), 5.15 (1H, d), 5.03 (1H, d), 4.99-4.90 (1H, m), 4.68-4.54 (1H, m), 3.31-3.17 (1H, m), 3.17-2.72 (4H, m), 2.45-2.35 (1H, m), 2.30-1.66 (5H, m), 1.44 (9H, s); Anal. Calcd for C33H36Cl2N4O9.0.5H2O: C, 55.62; H, 5.23; N, 7.86; Cl, 9.95. Found: C, 55.79; H, 5.15; N, 7.80; Cl 9.81. MS (ES+) 729/7/5 (M+Na), 707/5/3 (M+1), 163 (100%).
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30](COCCOC)[C:29](=[O:37])[O:28][N:27]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:40][C:41]([C:43]1[CH:52]=[CH:51][CH:50]=[CH:49][C:44]=1[C:45]([O:47]C)=[O:46])=[O:42].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:37])[O:28][N:27]=4)=[CH:18][CH:19]=3)[C:8](=[O:12])[N:9]([CH2:40][C:41]([C:43]3[CH:52]=[CH:51][CH:50]=[CH:49][C:44]=3[C:45]([OH:47])=[O:46])=[O:42])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1C(=O)CBr
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccccc3C(=O)O)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
To a mixture of 6-ethyl-1-[(2′-{4-[(2-methoxyethoxy)methyl]-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl}biphenyl-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), methyl 2-(bromoacetyl)benzoate (1.06 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (0.18 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, tetrahydrofuran (15 mL), methanol (15 mL) and 1N aqueous sodium hydroxide solution (10 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), N,N′-carbonyldiimidazole (0.2 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.18 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:26])([CH:23]([CH3:25])[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31].[Cl-].[Na+]>C1COCC1>[CH2:31]([O:26][C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:7][C:2]=1[Cl:1])([CH:23]([CH3:24])[CH3:25])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC(C)C(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(Cn1cncn1)(c1ccc(Oc2ccc(Cl)cc2)cc1Cl)C(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol (0.50 g) in 15 mL of THF was added sodium hydride (40 mg) at room temperature. The reaction mixture was then stirred for 30 min followed by the addition of allyl bromide (130 mg) and stirred at room temperature for 18 hours, then at 70° C. for 6 hours and then at 120° C. for 10 hours. An aq. solution of sodium chloride was then added, the mixture was extracted with dichloromethane, dried, evaporated. The crude residue was purified by flash column chromatography on silica gel to give 1-[2-allyloxy-2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-methyl-butyl]-1,2,4-triazole as a colorless oil (136 mg, 27%; HPLC-MS Rt=1.43 min; masse=432).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.FC(F)(F)S(O)(=O)=O.[I:17]N1C(=O)CCC1=O.[OH-].[Na+]>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:17]
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncnc(Cl)c1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-chloropyrimidin-4-amine (5.29 g, 40.8 mmol) and trifluoro-methane sulfonic acid (40 mL, 452 mmol) was added N-iodosuccinimide (9.19 g, 40.8 mmol). The mixture was stirred for 3 h at rt. The mixture was poured into 50 mL of ice containing 15 g of NaOH with stirring for 10 min. The resulting precipitate was filtered washed with water, triturated in DCM and collected by filtration to give 6-chloro-5-iodopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H); LC-MS (ESI) m/z 255.9 [M+H]+.