Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[S:31][CH:32]=[CH:33][N:34]=4)=[O:28])=[C:22]([F:35])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:36]#[N:37])C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[C:36]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:28])=[C:22]([F:35])[CH:21]=1)#[N:37]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
The N-(4-(7-benzyloxy-6-cyanoquinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea (5.53 g) synthesized in Example 141 was dissolved in TFA (55 ml), and then thioanisole (5.5 ml) was added and the mixture was heated and stirred at 70° C. for 6 hours. After cooling the reaction solution and concentrating it under reduced pressure, sodium bicarnobate water and methanol were added and the precipitated crystals were filtered. These were washed with diethyl ether to obtain 3.63 g of the title compound (80% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:22][C:12]1[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]=1
Reactant: C1CCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCCCC1
Yield: 51.2 %

Procedure:
Piperidine (0.198 mL; 2.00 mmol) was added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL) and the reaction mixture was irradiated in a microwave oven at 100° C. for 30 min. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.094 g (51%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].NC(N)=[S:24].[OH-].[Na+].Cl>O>[SH:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]
Reactant: CCOP(=O)(CCCCCCCCCCCCBr)OCC
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOP(=O)(CCCCCCCCCCCCS)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.5 %

Procedure:
In the second step, diethyl 12-bromododecylphosphonate (20.01 g; 51.9 mmol) is reacted, under an inert atmosphere, with thiourea (4 g; 51.9 mmol) in 200 ml of water at 100° C. with stirring for 12 hours. After cooling, a solution of sodium hydroxide (2.07 g; 51.9 mmol) in 100 ml of water is added dropwise and the reaction mixture is refluxed for 3 hours. After cooling to room temperature, hydrochloric acid solution (32%) is added dropwise to pH 1. The solution is then stirred for 24 hours. The organic phase is then recovered with 100 ml of CH2Cl2, washed with distilled water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The yellow oil obtained is purified by chromatography on a column of silica gel (eluent: hexane/8% EtOAc) to give 10.8 g (n=38.16 mmol) of diethyl 12-mercaptododecylphosphonate (52% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.Cl.[N:11]1([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:19]=[C:18]2[CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:14][CH2:13][CH2:12]1.C(N(C(C)C)C(C)C)C>C(#N)C>[N:11]1([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[N:19]=[C:18]2[CH:32]2[CH2:33][CH2:34][N:35]([C:7]3[N:6]=[CH:5][N:4]=[C:3]([NH2:9])[C:2]=3[Br:1])[CH2:36][CH2:37]2)[CH2:12][CH2:13][CH2:14]1
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: Nc1ncnc(Cl)c1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncnc(N2CCC(c3nc(-c4ccnc(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 5-Bromo-6-chloro-pyrimidin-4-ylamine (53.00 mg; 0.25 mmol; 1.00 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridine hydrochloride (4) (133.56 mg; 0.25 mmol; 1.00 eq.), and ethyl-diisopropyl-amine (0.23 ml; 1.27 mmol; 5.00 eq.) in ACN 3 ml was stirred at 80° C. for overnight. Purified by HPLC (basic), collected title compound, 30 mg, yield, 21%. LC-MS: (M+1=551, obsd.=551).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6](=[N:7]N)[C:5](=[N:9][OH:10])[C:4]([CH3:12])([CH3:11])[O:3]1.Cl.N[OH:16]>O>[CH3:1][C:2]1([CH3:13])[C:6](=[N:7][OH:16])[C:5](=[N:9][OH:10])[C:4]([CH3:12])([CH3:11])[O:3]1
Reactant: CC1(C)OC(C)(C)C(=NO)C1=NN
Reactant: NO
Agent: Cl
Solvent: O
Product: CC1(C)OC(C)(C)C(=NO)C1=NO
Yield: 86 %

Procedure:
10.0 g (54 mmol) of commercially available 2,2,5,5-tetramethyl-3,4-(2H, 5H)-furandione hydrazone oxime are heated under reflux for 2 hours with 75 g (1.1 mmol) of hydroxylamine hydrochloride in 800 ml of water. The precipitated product is filtered off with suction and washed with water. 8 g (86%) of 2,2,5,5-tetramethyl-3,4(2H, 5H)-furandione dioxime are obtained as a mixture of 2 isomers, m.p. 252° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]#[N:25])[CH2:19][CH2:18]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1.O1CCC[CH2:27]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(#N)C>[CH3:27][N:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]#[N:25])[CH2:21][CH2:22]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1
Reactant: N#CC[C@H]1CC[C@H](n2c(C3CNC3)nc3cnc4ccsc4c32)CC1
Reactant: C1CCOC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CN1CC(c2nc3cnc4ccsc4c3n2[C@H]2CC[C@H](CC#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [trans-4-(2-azetidin-3-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile (14 mg, 0.038 mmol) in methanol (0.5 mL)/tetrahydrofuran (0.5 mL)/acetonitrile (0.5 mL) was added 37% aq. formaldehyde solution (12 μL, 0.16 mmol). The resulting mixture was stirred at room temperature for 10 min before sodium triacetoxyborohydride (16 mg, 0.077 mmol) was added. The mixture was stirred at room temperature for 1 h and then diluted with MeOH and purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.8 mg, 6%). LCMS calculated for C20H24N5S (M+H)+: m/z=366.2. Found: 366.1.
Reaction SMILES: C([NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1)(=O)C.Cl.[CH2:21](O)C>>[NH2:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH2:12][CH3:21])=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OC
Yield: 91 %

Procedure:
To a solution of methyl 4-acetamido-2-methoxy-5-nitrobenzoate (135 mg, 0.50 mmol) in ethanol 10 ml) was added concentrated hydrochloric acid (0.5 ml) dropwise and the mixture refluxed under nitrogen overnight. The reaction mixture was then cooled, the solvents removed and the residue purified by column chromatography (silica gel), eluting with 1:1 ethyl acetate/hexane to give ethyl 4-amino-2-methoxy-5-nitrobenzoate as a yellow solid (110 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Br:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:35])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-bromoquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation D, 5 g, 13.1 mmol) and triethylamine (1.59 g, 15.7 mmol) in CH2Cl2 (120 mL) was added over 40 minutes to a solution of triphosgene (4.3 g, 14.4 mmol) in CH2Cl2 (80 mL) at 0° C. using ice-bath. The reaction mixture was stirred for 20 minutes at this temperature then was quenched with saturated aqueous NaHCO3, stirred for 5 minutes and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and solvent was evaporated to obtain the title compound. Yield: 3.2 g (60%); 1H NMR (DMSO-d6, 300 MHz): δ 11.835 (s, 1H), 8.783 (s, 1H), 7.908-7.938 (d, 1H, J=9 Hz), 7.810-7.838 (d, 2H, J=8.4 Hz), 7.665-7.694 (d, 2H, J=8.7 Hz), 7.613-7.650 (dd, 1H, J=9 Hz, 1.8 Hz), 6.949-6.955 (d, 1H, J=1.8 Hz), 1.609 (s, 6H); MS: m/z 406 (M+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3C)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 119a (32 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (23 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.69-1.94 (m, 2 H) 2.02 (s, 3 H) 2.32 (s, 3 H) 2.99 (t, J=7.35 Hz, 2 H) 5.14 (s, 2H) 6.32 (d, J=6.99 Hz, 1 H) 6.98-7.30 (m, 7 H) 7.41 (dd, J=11.40, 8.82 Hz, 4 H) 7.80 (d, J=8.82 Hz, 1 H) 8.38 (d, J=6.99 Hz, 1 H) 8.97 (d, J=8.46 Hz, 1 H) 9.98 (s, 1 H) 11.02 (s, 1 H) 14.37 (s, 1 H); MS (ESI+) m/z 549(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[O:17][C:18]([C:20](O)=[O:21])=[CH:19][C:13]=3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.[CH:41]1[CH:42]=[CH:43][C:44]2[N:49](O)N=[N:47][C:45]=2[CH:46]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:47][C:45]1[CH:46]=[CH:41][CH:42]=[CH:43][C:44]=1[NH:49][C:20]([C:18]1[O:17][C:14]2[CH2:15][CH2:16][N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:12][C:13]=2[CH:19]=1)=[O:21]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCc3oc(C(=O)O)cc3C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCc3oc(C(=O)Nc4ccccc4N)cc3C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylic acid (1.0 eq) obtained from step II in DMF was added Et3N (2.2 eq.), EDCI (1.2 eq) and HOBt ((1.2 eq) and reaction was stirred for 1 h Phenylene diamine was added to reaction mass and stirred for overnight. Reaction was quenched with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]#[N:15])=[CH:8][CH:7]=1)=[O:4].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:23])([C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[NH:26][N:25]=[N:24][N:15]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CCc2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 130 °C
Yield: 43.3 %

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-cyanoethyl)phenyl]butanamide (3.9 g), sodium azide (3.7 g), ammonium chloride (3 g) and dimethylformamide (60 mL) was stirred under a nitrogen atmosphere and heated in a 130° C. oil bath for 48 hours. Water (300 mL) was added to the hot mixture to dissolve all suspended salts and the solution was allowed to cool to room temperature. More water was added and the precipitate was collected by filtration. The tan solid was dried at 65° C. in vacuo overnight and recrystallized from a hexane/tetrahydrofuran mixture to give 1.9 g (43% yield) of the title compound as a tan solid, m.p. 161°-162° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[N:16](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a mixture of 3-(4-nitrophenyl)propionic acid (13.45 g), N,N-dimethylformamide (0.1 mL) and tetrahydrofuran (300 mL) was added dropwise oxalyl chloride (10.5 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. and concentrated. The obtained residue was dissolved in tetrahydrofuran (50 mL) and added dropwise to a mixture of 25% aqueous ammonia (100 mL) and tetrahydrofuran (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-(4-nitrophenyl)propanamide as colorless crystals (11.80 g, yield 88%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: C(Cl)Cl.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N([C@@:13]1(O)[C@@H:19](O)[C@H:18](O)[C@@H:17]([CH2:22]O)O[CH:14]1O)=[N+]=[N-]>C(Cl)(Cl)(Cl)Cl>[C:6]1([CH:13]2[CH2:19][CH2:18][CH2:17][CH:22]=[CH:14]2)[CH:5]=[CH:4][CH:9]=[CH:8][CH:7]=1
Reactant: CCCCCC
Reactant: [N-]=[N+]=N[C@]1(O)C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C1=CC(c2ccccc2)CCC1

Procedure:
TLC Rf=0.67 (10% CH2Cl2/hexane); IR (CCl4) 3088 (m),3063 (m),3025 (s), 2938 (s), 2863 (s), 2838 (s), 1656 (w), 1606 (m), 1543 (m); 1H NMR (CDCl3) δ0.85-2.09 (m, 6H), 3.38 (bs, 1H), 5.70 (dd, J=10.0, 2.1, 1H), 5.86-5.88 (m, 1H), 7.16-7.30 (m, 5H); 13C NMR (CDCl3) δ21.2, 22.7, 32.6, 41.8, 125.9, 127.7, 128.2, 128.3, 130.2, 146.6; LRMS (EI) 159 ((M+1), 15), 158 ((M+), 100), 143 (43), 129 (79); HRMS (EI) calculated for C12H14 158.1096 (M+), found 158.1098. The IR, 1H NMR and 13C NMR, and MS matched spectral data reported by Arnold, D. R. and Mines, S. A., Can. J. Chem. 67:689-698 (1989).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Br[C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C(COC)OC.CCOCC>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Oc2nccs2)CC1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 5.67 g) in dimethoxyethane (40 ml) was added a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (23.9 g) in dimethoxyethane (60 ml) over 30 minutes, and the mixture was stirred for an additional 1 hour. To the mixture was added 2-bromothiazole (15.0 g), and the mixture was refluxed for 4 hours. After cooling, the resulting pale brown suspension was diluted with ether (300 ml) and the mixture was filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (eluent; 15% ethyl acetate in n-hexane) to give the title compound (22.1 g) as a yellow oil.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH2:26][CH:27]([O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=O)=O.[N-:38]=[N+:39]=[N-:40].[Li+].N(CC(NC(OC(C)(C)C)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>CN(C)C=O>[N:38]([CH2:6][CH:7]([CH2:26][CH:27]([O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N+:39]=[N-:40]
Reactant: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)CC(C)OC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])CC(C)OC(=O)c1ccccc1
Yield: 96.6 %

Procedure:
A mixture of the previously obtained 2-(2-benzoyloxypropan-1-yl)-3-n-hexadecylthiopropyl methanesulfonate m12a and 1.297 g (26.5 mM) of lithium azide in 50 ml of dimethylformamide is allowed to react by the same procedure as described in (53) and 1.291 g (96.6% yield) of the titled compound m12b is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Product: c1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and iodobenzene: ESMS m/e: 193.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21]>CS(C)=O>[CH2:17]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 70 °C
Yield: 94895.6 %

Procedure:
To a stirred solution of 4-(4-bromophenyl)phenol (25.5 g, 0.102 mmol) in 400 mL of dimethylsulfoxide was added 2.5N NaOH (40.9 ml, 0.102 mol) followed by n-pentyl bromide (12.7 mL, 0.102 mol). The resulting mixture was heated at 70° C. for a period of 18 h. After cooling, the solution was partitioned between ethyl acetate (1000 ml) and water (500 ml). The organic phase was washed with water (3×) and brine and dried with magnesium sulfate. The solvent was removed in vacuo to give 30.9 g of 4-(4-n-pentoxyphenyl)-bromobenzene: 1H NMR (400MHz, DMSO-d6) δ0.93 (t, 3H, J=7.2 Hz), 1.41 (m, 4H), 1.79 (m, 2H), 3.97 (t, 2H, J=6.6 Hz), 6.94 (d, 2H, J=8.8 Hz), 7.39 (d, 2H, J=8.6 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.51 (d, 2H, J=8.6 Hz).
Reaction SMILES: [C:1](=O)([S:3][CH2:4][P:5]([O:11][CH:12]([CH3:14])[CH3:13])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2].C[O-].[Na+].Br[CH:20](C)C>CO>[CH:1]([S:3][CH2:4][P:5](=[O:6])([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9])([CH3:20])[CH3:2]
Reactant: CC(=O)SCP(=O)(OC(C)C)OC(C)C
Reactant: CC(C)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OP(=O)(CSC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of S-(diisopropoxyphosphoryl)methyl ethanethioate (1.00 g, 3.93 mmol; Example 206, Step A) in methanol (39.3 mL) at 0° C. was added sodium methoxide (7.87 mL, 3.93 mmol), followed by 2-bromopropane (0.44 mL, 4.72 mmol). The reaction was stirred at 25° C. for 16 hours. The reaction solvent was removed in vacuo and the crude material was partitioned between water and EtOAc (2×) and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (40 g column, eluent: 0 to 75% DCM/hexanes) provided the title compound as an off-white solid.
Reaction SMILES: [CH:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[CH2:2].I[CH2:15]Cl.C([Zn]CC)C>ClC(Cl)C>[CH:1]1([O:3][C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:15][CH2:2]1
Reactant: C=COc1cccc(C(=O)OC)c1
Reactant: ClCI
Agent: CC[Zn]CC
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(OC2CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(vinyloxy)benzoate (0.83 g, 3.99 mmol) in dichloroethane (20 mL) was added iodochloromethane (1.09 mL, 14.9 mmol). The solution was cooled to 0° C. and diethyl zinc (1.0 M in hexanes, 7.48 mL, 7.48 mmol) was added. The cooling bath was removed and the reaction was stirred at rt for 30 min. The reaction mixture was quenched with 1N HCl, extracted with methylene chloride (three times), dried with MgSO4 and concentrate under vacuum to afford the desired product.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C@@H:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[N:22]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)[N:24]=3)[CH2:16]1)[CH3:14].C(N(CC)CC)C.[C:55](O)(=[O:59])[C@H:56]([CH3:58])[OH:57].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:25]2[N:24]=[C:23]3[C:28]([N:29]=[C:21]([N:17]4[CH2:18][CH2:19][N:20]([C:55](=[O:59])[C@@H:56]([OH:57])[CH3:58])[C@@H:15]([CH2:13][CH3:14])[CH2:16]4)[N:22]3[CH2:43][C:44]([F:47])([F:46])[F:45])=[C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)=[CH:37][N:38]=1
Reactant: C[C@H](O)C(=O)O
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)[C@H](C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (80 mg, 0.42 mmol) was added to an N,N-dimethylformamide solution (5 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (136 mg, 0.28 mmol), triethylamine (0.096 ml, 0.69 mmol), L-lactic acid (30 mg, 0.33 mmol), and 1-hydroxybenzotriazole (47 mg, 0.30 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer washed with water and saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:10) to give the title compound (31 mg) as a pale yellow solid.