Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[CH:11][N:10]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: C1=COCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(-c2ncn(C3CCCCO3)c2-c2ccc(OC)cc2)cc1
Yield: 81.6 %

Procedure:
14.17 g of 4,5-bis(4-methoxyphenyl)imidazole is suspended in 250 ml of absolute 1,2-dichloroethane and combined with 16 g of 3,4-dihydro-2H-pyran as well as 0.5 ml of tin tetrachloride. The mixture is heated to reflux under agitation for 12 hours, then allowed to cool, and poured into 500 ml of cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate, and concentrated under vacuum. The residue is dissolved in dichloromethane and subjected to hexane precipitation. The sediment is dissolved in ether. The solution is clarified with activated carbon, concentrated under vacuum, and made to crystallize, thus producing 15.03 g of 4,5-bis(4-methoxyphenyl)-1-(tetrahydropyran-2-yl)imidazole, mp 127°-128°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].CC(=O)CC>C(OCC)C>[Cl:20][CH2:19][CH2:18][O:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9]
Reactant: Oc1c(Br)cc(F)cc1Br
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Fc1cc(Br)c(OCCCl)c(Br)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 2,6-dibromo-4-fluoro-phenol (55 g, 0.20 mol), potassium carbonate (60 g, 0.43 mol), 1-bromo-2-chloroethane (32.5 g, 0.23 mol) and 2-butanone (500 mL) was heated to reflux for 2 hours and allowed to cool to ambient temperature. The solids were filtered and the solvent was removed under vacuum to afford an oil. The oil was dissolved in diethyl ether (300 mL) and washed with water, dried over anhydrous magnesium sulfate, charcaolized, and filtered through Solka floc to afford 65.9 g (97.2%) of an oil; MS EI m/e 330/332/334/336 (M+); 1H NMR (.CDCl3) δ 3.89 (2H, t, J=6.1 Hz), 4.23 (2H, t, J=6.1 Hz), 7.28 (2H, d, J=7.5 Hz).
Reaction SMILES: C(N[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(CC)C.[N+](C1C=CC=C[C:26]=1[OH:31])([O-])=O.[N+](C1C=C(C(C)(C)C)C=C([N+]([O-])=O)C=1O)([O-])=O.CI.C(=O)([O-])[O-].[K+].[K+]>>[C:15]([C:9]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]([O:31][CH3:26])=[C:7]([N+:19]([O-:21])=[O:20])[CH:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
An alternative synthesis for N-sec-butyl-4-tert-butyl-2,6-dinitroaniline is set forth in U.S. Pat. Nos. 4,289,907 and 4,395,572 to Chan. The starting material in this synthesis is a nitrophenol such as 2,6-dinitro-4-tert-butylphenol. The nitrophenol is methylated by reaction with methyl iodide/potassium carbonate to produce 4-tert-butyl-2,6-dinitroanisole. The 4-tert-butyl-2,6-dinitroanisole is then reacted with sec-butylamine to produce N-sec-butyl-4-tert-butyl-2,6-dinitroaniline. While effective in producing the desired product, this process also suffers from a number of distinct disadvantages.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH2:6][CH2:5]2.[C:13](=[O:16])([O-])[O-].[K+].[K+]>C(N)C1C=CC=CC=1>[CH2:8]([NH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:11]=1)[C:13](=[O:16])[NH:7][CH2:6][CH2:5]2)[C:9]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCc2cc(F)ccc21
Agent: [K+]
Solvent: NCc1ccccc1
Product: O=C1NCCc2cc(NCc3ccccc3)ccc21
Yield: 35 %

Procedure:
A solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (300 mg, 1.81 mmol) and potassium carbonate (550 mg, 3.98 mmol) in benzylamine (1.5 ml) was stirred at 180° C. in a microwave for 2 hrs. The solvent was evaporated and the resulting residue partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with brine (10 ml), then dried (MgSO4) and evaporated in vacuo. The crude residue was purified by preparative HPLC (Method A) to yield the title compound as a colourless solid (80 mg, 18%). HPLC retention time 3.81 min. Mass spectrum (ES+) m/z 253 (M+H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([CH:9]([CH2:15][C:16]([OH:18])=O)[C@@H:10]([C:12]([OH:14])=O)N)[CH3:8].[CH2:19]1COCC1>>[CH2:7]([CH:9]([CH2:15][CH2:16][OH:18])[CH:10]([CH3:19])[CH2:12][OH:14])[CH3:8]
Reactant: C1CCOC1
Reactant: CCC(CC(=O)O)[C@H](N)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(CCO)C(C)CO
Temperature: 36 °C
Reaction time: 6 h

Procedure:
To a slurry of LAH (2.06 g, 54.29 mmol) in THF (60 mL) was added 3-ethylglutamic acid (3.5 g, 21.71 mmol) dropwise at 0° C. over 20 min. The reaction was heated to 36° C. for 18 h. The reaction slurry (gray) was cooled to 0° C. and quenched with H2O (3 mL) then washed with 1N NaOH (9 mL) and H2O (3 mL). It was then stirred for 6 h at 25° C. to obtain an off-white slurry. The slurry was filtered and the mother liquor was further dried over MgSO4, filtered and concentrated in vacuo to obtain 3-ethyl-2-methylpentane-1,5-diol as a crude yellow oil (2.85 g, 89.17%). Mass Spectrum (+ESI): 170 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:18]=[CH2:19])=[C:4]([NH:10][CH:11]([CH:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH:18]=[CH2:19])=[C:4]([NH:10][CH:11]([CH:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C=Cc1c(NC(C(=O)O)C(C)O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: C=Cc1c(NC(C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
2-(3-Chloro-4-cyano-2-vinyl-phenylamino)-3-hydroxy-butyric acid (690 mg, 3.8 mmol) and 4-cyanobenzohydrazide (673 mg, 4.18 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (514 mg, 3.8 mmol), TEA (0.8 mL, 5.7 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (1.09 g, 5.7 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×60 mL), 5% NaHCO3 (2×60 mL) followed by water (60 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (0.79 g, 49%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.92 (br s, 1H), 9.49 (br s, 1H), 7.99 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 6.53 (dd, J=12 and 18 Hz), 5.99 (d, J=9 Hz, 1H), 5.73 (dd, J=2 and 12 Hz, 2H), 5.64 (dd, J=2 and 18 Hz), 4.29-4.22 (m, 1H), 4.01-3.99 (m, 1H) and 1.20 (d, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:27]([N:29]([CH2:35][CH3:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:28].FC(F)(F)C(O)=O>C(#N)C>[CH2:27]([N:29]([CH2:35][CH3:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:16]1[N:15]=[C:14]2[N:13]([CH2:24][CH3:25])[C:12](=[O:26])[N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH2:20][C:19]2=[CH:18][N:17]=1)[CH3:28]
Reactant: CCN(CC)CCCCN
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(CC)CCCCNc1ncc2c(n1)N(CC)C(=O)N(c1cc(OC)cc(OC)c1)C2
Temperature: 90 °C
Yield: 56 %

Procedure:
A mixture of 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (0.5 g, 1.33 mmol), 4-diethylaminobutylamine (0.38 g, 2.66 mmol,) and trifluoroacetic acid (0.31 g, 2.66 mmol) in acetonitrile (6 mL) was heated in a sealed tube at 90° C. for 18 hours. The solvent was removed under reduced pressure and the residue taken up in 1N HCl. The solution was made basic with 50% NaOH and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by radial chromatography eluting with a solvent mixture of ethyl acetate/methanol/ethyl (89:10:1 v/v/v) to give 0.34 g (56%) of the titled compound: mp 83-85° C. Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe=450° C.) (m+1)/z 458.2
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].C(Cl)[Cl:55]>C(O)(=O)C>[ClH:55].[ClH:55].[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:12]2[CH2:13][CH2:14][N:15]([CH2:36][C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[CH2:16][CH2:17]2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:9][CH:10]=1)[CH3:30]
Reactant: O=Cc1cccs1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3cccs3)CC2)cc1
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution of compound 1 (0.99 mmol) in methylene chloride (10 ml) was added 2-thiophenecarboxaldehyde (190 ul; 1.98 mmol) followed by acetic acid (0.1 ml; 1%). The mixture was stirred 30 minutes then sodium triacetoxyborohydride (0.63 g; 2.97 mmol) was added and the reaction mixture stirred overnight. The reaction mixture was neutralized with sodium hydroxide 2N and extracted with methylene chloride (3×). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O (TFA as the buffer) gave 115 mg of desired product (TFA salt).
Reaction SMILES: [CH3:1][C:2]1[C:6](I)=[C:5]([CH3:8])[O:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.BrC1C=C(C2C=NC=CC=2)C=CC=1>>[Br:9][C:10]1[CH:15]=[C:14]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:8])[CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1noc(C)c1I
Agent: Brc1cccc(-c2cccnc2)c1
Product: Cc1noc(C)c1-c1cccc(Br)c1
Yield: 119 %

Procedure:
The reaction of 3,5-dimethyl-4-iodoisoxazole (Kochetkov, N. K. Zhurnal Obschchie Khimii, 31, 2167-2172 (1961)) (2.4 g, 11 mmol) with 3-bromophenylboronic acid (2.24 g, 11 mmol) using the procedure for the preparation of 3-(3'-bromophenyl)pyridine gave 3.3 g crude 4-m-bromophenyl-3,5-dimethylisoxazole. After a quick filtration on Si gel (eluting with CH2Cl2), the material was further purified by preparative TLC on 12-1000μ Si Gel GF plates (eluting with 10% acetone/hexane and extracting with 10% MeOH/CH2Cl2), to provide 1.2 g of the arylated isoxazole. Sublimation (ambient to 70° C., high vacuum) of 0.5 g provided 404 mg of analytically pure material.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]CN=C=NCCCN(C)C.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:13][CH:12]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[4-(tert-Butoxycarbonyl)phenyl]acetic acid (2.94 g, 12.4 mmol) and DMAP (152 mg, 1.24 mmol) were dissolved in CH2Cl2 (50 mL) and cooled to 0° C. EDCI (3.10 g, 16.2 mmol) and MeOH (660 μL, 16.2 mmol) were added. After stirring for 30 min at 0° C., the reaction was allowed to warm to room temperature and stirred 2 h. The mixture was then diluted with CH2Cl2, washed (sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica gel (0-10% EtOAc/hexanes) afforded tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate as a colorless oil. 1H NMR (CDCl3) δ 7.93 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 3.68 (s, 3H), 3.66 (s, 2H), 1.57 (s, 9H). MS (ESI) calcd [M+Na]+ 273.1, found 273.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([N:15]=O)=[C:13]([CH3:17])[N:12]=[C:7]12.C(O)(=O)C>O.[Zn]>[NH2:15][C:14]1[N:6]2[CH:5]=[CH:4][C:3]3[C:8]([C:7]2=[N:12][C:13]=1[CH3:17])=[CH:9][CH:10]=[CH:11][C:2]=3[Cl:1]
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1N=O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N
Yield: 80.6 %

Procedure:
Zinc powder (10.2 g) was added portionwise to a mixture of 7-chloro-2-methyl-3-nitrosoimidazo[2,1-a]isoquinoline (7.7 g) and acetic acid (100 ml) in water (77 ml) over a period of 7 hours and then the mixture was filtered by suction. The filtrate was evaporated in vacuo and the residue was extracted with chloroform after an addition of aqueous sodium bicarbonte to it. The extract was washed with water and evaporated in vacuo. The residual solid was washed with ethyl acetate and dried in a desiccator to give 3-amino-7-chloro-2-methylimidazo[2,1-a]isoquinoline (5.85 g).
Reaction SMILES: B.[CH2:2]([O:18][CH2:19][C:20]1[O:25][CH2:24][CH2:23][CH2:22][CH:21]=1)[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][CH2:16][CH3:17].[OH-:26].[Na+].OO>O1CCCC1.O>[CH2:2]([O:18][CH2:19][C@H:20]1[C@H:21]([OH:26])[CH2:22][CH2:23][CH2:24][O:25]1)[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][CH2:16][CH3:17]
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCCCOCC1=CCCCO1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOC[C@@H]1OCCC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11 ml of a 1M tetrahydrofuran solution of borane was added dropwise, whilst ice-cooling, to a solution of 5.53 g of 6-hexadecyloxymethyl-3,4-dihydro-2H-pyran (prepared as described in Preparation 1) dissolved in 12 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours, after which 4 ml of a 3N aqueous solution of sodium hydroxide were added to it, and then 4 ml of 30% hydrogen peroxide were added dropwise into it at 30°-40° C. The reaction mixture was then stirred at room temperature for 1 hour, after which it was poured in water. The mixture was then washed with a saturated aqueous solution of sodium chloride, and then the organic layer was separated, dried and condensed by evaporation under reduced pressure. The oily residue was subjected to column chromatography through 100 g of silica gel. The fraction eluted with mixtures of ethyl acetate and hexane ranging from 1:5 to 1:2 by volume gave 5.18 g of the title compound as crystals. Recrystallization from hexane gave needles, melting at 41.5°-43° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[F:10].[C-:11]#[N:12].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[CH:4][C:3]=1[F:10]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1Br
Agent: [K+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (1 g, 3.73 mmol) in ethanol (30 mL) was added KCN (0.243 g, 3.73 mmol). The resulting mixture was stirred at 60° C. After 3 h, LCMS analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in EA (80 mL) was washed with H2O (30 mL) and brine (30 mL). The organic layer was dried and concentrated to give the crude product, which was purified by silica column chromatography (PE/EA=10/1) to yield a white solid of 2-(4-bromo-3-fluorophenyl)acetonitrile (0.78 g, 2.96 mmol, 79.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.63 (t, J=7.8 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.12 (d, J=9.6 Hz, 1H), 3.92 (s, 2H); ES-LCMS m/z 214.0 (M+H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]([CH3:16])=[N:15][C:10]2=[CH:9][CH:8]=1)(=[O:4])=[O:3].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:16][C:14]1[S:13][C:11]2[C:10]([N:15]=1)=[CH:9][CH:8]=[C:7]([CH2:6][P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:12]=2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1nc2ccc(COS(C)(=O)=O)nc2s1
Solvent: CC#N
Product: CS(=O)(=O)[O-]
Product: Cc1nc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2s1

Procedure:
A solution of the mesylate of Step 7 (1.68 mmol) and triphenylphosphine (660 mg, 2.52 mmol) in 8 mL of anhyd. CH3CN was heated at reflux for 2 hr. The solvent was evaporated and the oil was swished in ether and the ether decanted twice. It was swished again in 25 mL ether over the weekend. The solvent was decanted to afford a very hygroscopic solid, which was dried under vacuum; yield: 732 mg, (84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:66]=[C:65]([CH:67]=[CH:68][C:69]([O:71][CH3:72])=[O:70])[CH:64]=[CH:63][C:4]=1[O:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:62])[C:50]2[CH:55]=[CH:54][C:53]([CH:56]=[CH:57][C:58]([O:60][CH3:61])=[O:59])=[CH:52][CH:51]=2)=[CH:44][C:14]=1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:43])[C:31]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[C:33]([N+:40]([O-])=O)[CH:32]=1)=[O:16].[Cl-].[NH4+]>[Zn].CO.O>[CH3:1][O:2][C:3]1[CH:66]=[C:65]([CH:67]=[CH:68][C:69]([O:71][CH3:72])=[O:70])[CH:64]=[CH:63][C:4]=1[O:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:62])[C:50]2[CH:51]=[CH:52][C:53]([CH:56]=[CH:57][C:58]([O:60][CH3:61])=[O:59])=[CH:54][CH:55]=2)=[CH:44][C:14]=1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:43])[C:31]1[CH:36]=[C:35]([NH2:37])[CH:34]=[C:33]([NH2:40])[CH:32]=1)=[O:16]
Reactant: COC(=O)C=Cc1ccc(C(=O)Oc2ccc(CCCCCCOOc3ccc(C=CC(=O)OC)cc3OC)c(C(=O)OCCCCCCCCCCCOC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)C=Cc1ccc(C(=O)Oc2ccc(CCCCCCOOc3ccc(C=CC(=O)OC)cc3OC)c(C(=O)OCCCCCCCCCCCOC(=O)c3cc(N)cc(N)c3)c2)cc1

Procedure:
0.997 g (1.00 mmol) 3,5-Dinitrobenzoic acid 11-[2-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]benzoyloxy]undecyl ester and 0 g (4.00 mmol) of ammonium chloride were suspended in 15 ml of a mixture consisting of methanol:water 9:1. 1.31 g (20.0 mmol) of zinc was then added in one portions. After 0.5 hour at room temperature 20 ml of a mixture consisting of methanol:water 9:1 is added to the thick suspension. After a further 21 hours the reaction suspension was partitioned between dichloromethane and water. The resulting suspension was filtered, the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water. The organic phase was then dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography of the residue on silica yield 3,5-Diaminobenzoic acid 11-[2-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]benzoyloxy]undecyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][N:25]=[C:24]([NH:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([NH:36][CH3:37])=[O:35])[N:23]=1.Cl.[F:42][C:43]1[CH:53]=[CH:52][C:46]([O:47][CH:48]2[CH2:51][NH:50][CH2:49]2)=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:28]([C:27]1[C:22]([N:50]2[CH2:51][CH:48]([O:47][C:46]3[CH:45]=[CH:44][C:43]([F:42])=[CH:53][CH:52]=3)[CH2:49]2)=[N:23][C:24]([NH:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([NH:36][CH3:37])=[O:35])=[N:25][CH:26]=1)#[N:29].[C:19]([C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])=[N:7][C:2]([N:50]2[CH2:51][CH:48]([O:47][C:46]3[CH:45]=[CH:44][C:43]([F:42])=[CH:53][CH:52]=3)[CH2:49]2)=[N:3][CH:4]=1)#[N:20]
Reactant: CNC(=O)c1cccc(Nc2ncc(C#N)c(Cl)n2)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2C#N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2nc(N3CC(Oc4ccc(F)cc4)C3)ncc2C#N)c1
Product: CNC(=O)c1cccc(Nc2ncc(C#N)c(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C

Procedure:
To the reaction mixture of 3-(2-chloro-5-cyanopyrimidin-4-ylamino)-N-methylbenzamide and 3-(4-chloro-5-cyanopyrimidin-2-ylamino)-N-methylbenzamide (172.7 mg, 0.600 mmol) and 3-(4-fluorophenoxy)azetidine hydrochloride (128 mg, 0.631 mmol) in a disposable sealed tube at RT was added 2-propanol (4 mL) followed by N,N-diisopropylethylamine (0.314 mL, 1.802 mmol). The resulting reaction mixture was heated to 84° C. for 4.5 h, cooled to RT, concentrated, adsorbed onto silica gel, purified using MPLC (25 g cartridge about 20% full, 40 g column, 0 to 80% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(5-cyano-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-2-ylamino)-N-methylbenzamide (19.3 mg) and 3-(5-cyano-2-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide (13.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:9]#[N:10].CO.[H][H]>[Pd].O1CCOCC1>[NH2:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[NH:5][CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1]
Reactant: N#Cc1ccc([N+](=O)[O-])c(NCc2ccccc2Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(N)c(NCc2ccccc2Cl)c1
Yield: 83.8 %

Procedure:
Fifty milligrams of 10% palladium on carbon were added to a mixed solution of 261 mg of 3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile, 15 ml of methanol and 3 ml of 1,4-dioxane to conduct the catalytic reduction in a hydrogen atmosphere at 3 atm. After the completion of the reaction, the reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The resulting solid material was washed with ether, and was collected through filtration to give 196 mg of 4-amino-3-[N-(2-chlorobenzyl)amino]benznitrile.