Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([N:13]=[C:14]=O)([CH3:12])[CH3:11])[CH:5]=1)=[CH2:3].[CH:16]1([N:22]=C=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:22]=[C:14]=[N:13][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([CH3:1])=[CH2:3])[CH:5]=2)([CH3:12])[CH3:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C=NC1CCCCC1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Product: C=C(C)c1cccc(C(C)(C)N=C=NC2CCCCC2)c1
Temperature: 150 °C

Procedure:
We combined 0.0830 g TPAO, 60.41 g of m-TMI, and 25.04 g cyclohexylisocyanate. After heating at 150° C. for 7 hours, IR showed nearly complete conversion of isocyanates to carbodiimides. 1H--NMR indicated the desired product contaminated with 1,3-dicyclohexylcarbodiimide, and 1,3-bis[2-(3-isopropenylphenyl)-2propyl]carbodiimide.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:19](=[O:34])[N:20]([CH3:33])[C@@H:21]([C:29](=[O:32])[NH:30][CH3:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([O:11][CH2:10][C@@H:9]([NH:7][CH3:6])[C:19]([N:20]([CH3:33])[C@@H:21]([C:29](=[O:32])[NH:30][CH3:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:34])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
N-((1R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)N-methylcarbamic acid tert-butyl ester (0.23 g; 0.476 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred for 10 min at room temperature. Methylene chloride (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.182 g of (2R)-3-Benzyloxy-N-methyl-2-(methylamino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)propionamide.
Reaction SMILES: Cl.[CH2:2]1[O:9][CH:8]2[CH:4]([CH2:5][NH:6][CH2:7]2)[O:3]1.[Cl:10][C:11]1[C:12]([F:41])=[C:13]([CH:38]=[CH:39][CH:40]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:36][CH3:37])=[C:22]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:35])[CH2:33]Cl)[CH:23]=2)[N:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:10][C:11]1[C:12]([F:41])=[C:13]([CH:38]=[CH:39][CH:40]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:36][CH3:37])=[C:22]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:35])[CH2:33][N:6]3[CH2:5][CH:4]4[O:3][CH2:2][O:9][CH:8]4[CH2:7]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: C1OC2CNCC2O1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CN1CC2OCOC2C1
Yield: 69.8 %

Procedure:
3,4-methylenedioxypyrrolidine hydrochloride (87 mg) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.25 g; prepared as described in Example 43) and diisopropylethylamine (0.2 ml) in acetonitrile (10 ml) and the mixture heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/isopropanol/triethylamine (97/2/1) to (95/4/1). The fractions containing the expected product were evaporated under vacuum to give the title product as a yellow solid (0.203 g; 70%); 1H NMR Spectrum: (CDCl3) 1.92-222 (m, 4H), 2.54-2.61 (m, 2H), 3.05-3.15 (m, 2H), 3.26-3.38 (q, 2H), 3.42-3.47 (m, 1H), 3.58-3.65 (m, 1H), 4.00-4.10 (m, 4H), 4.47-4.55 (m, 3H), 4.65-4.72 (m, 1H), 4.84 (s, 1H), 5.02 (s, 1H), 7.11-7.22 (m, 2H), 7.24 (s, 1H), 7.96-8.02 (m, 1H), 8.38 (s, 1H), 8.61 (s, 1H), 8.63 (s, 1H); Mass Spectrum: (M+H)+ 558.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[F:13])[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CCOCC>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[F:13])[C:3]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCc1ccc2c(-c3ccc(O)cc3)c(F)c(F)cc2c1F
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3c(F)c(CCCCCCCC)ccc23)cc1

Procedure:
From 4-(2,3,5-trifluoro-6-octylnaphthalen-1-yl)phenol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[C:10]([Cl:15])[CH:9]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Potassium carbonate (0.98 g, 7.086 mmol) was added to a solution of 4-bromo-2-chlorophenol (0.7 g, 3.374 mmol) and 4-methoxybenzylbromide (0.51 mL, 3.543 mmol) in acetone (20 mL) and the mixture was stirred at room temperature overnight. The solid phase was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc and aqueous NaOH (2 M). The organic layer was washed with water and brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 99/1) to give 0.937 g (85% yield) of 4-bromo-2-chloro-1-(4-methoxy-benzyloxy)-benzene as yellow solid.
Reaction SMILES: [CH3:1][NH2:2].C([Li])CCC.[C:8](/[C:16](=[C:19](/OC)\[CH3:20])/[C:17]#[N:18])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8](/[C:16](=[C:19](/[NH:2][CH3:1])\[CH3:20])/[C:17]#[N:18])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Reactant: CN
Agent: [Li]CCCC
Product: CN/C(C)=C(\C#N)C(=O)c1ccccc1

Procedure:
In the glass liner of a stainless steel bomb cooled to -78° is condensed 10 ml. of methylamine. To this is added 0.5 ml. of 2 M n-butyllithium (in hexane), followed by 5.0 g. of 2-benzoyl-3-methoxycrotononitrile. The bomb is sealed and heated on a steam bath overnight. The bomb is then cooled, opened and the contents evaporated. The residue is dissolved in chloroform, passed through a Magnesol® pad and the filtrate is evaporated. The residue is recrystallized from chloroform-hexane yielding the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH:16]=[CH2:15])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: C=CCBr
Reactant: Cc1ccc(O)c2c1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1ccc(C)c2c1C(=O)CC2

Procedure:
Into a solution of 36 g of 4-methyl-7-hydroxy-1-indanone and 17.6 g of potassium hydroxide in 650 ml of methanol was added 25 ml of allyl bromide, and the mixture was refluxed by heating for 6 hours. The insoluble matters in the reaction mixture were removed by filtration, then the solvent was removed by evaporation. The residue obtained was extracted with chloroform-water, and the chloroform layer was collected by separation, then the solvent was removed by evaporation. The residue thus obtained was washed with ether and purified by means of a column chromatography to obtain 32 g of 4-methyl-7-allyloxy-1-indanone.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26]([CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)[CH3:27]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: CNC
Product: Cc1ccc(-c2cc(CN(C)C)c(=O)n(CC(C)C)n2)cc1

Procedure:
Following the procedure of Example 7, 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a slightly yellow oil (yield: 96.6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[C:41]1([NH:40][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[Se:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1[Se]Cc1ccccn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccccc1[Se]Cc1ccccn1

Procedure:
To a solution of 7 g (0.024 mol) 2-(2-picolylseleno)benzoic acid (from Example 1) and 2.4 g (0.024 mol) triethylamine in 40 ml dichloromethane which has been cooled to 0°-5° C. is added 6 g (0.024 mol) bis(2-oxo-3-oxazolidinyl)phosphoryl chloride in solid form as one portion. After stirring for 20 minutes a solution of 2.2 g (0.024 mol) aniline in 5 ml dichloromethane and a solution of 2.4 g (0.024 mol) triethylamine in 5 ml dichloromethane and a solution of 2.4 g (0.024 mol) triethylamine in 5 ml dichloromethane are added dropwise within 5 min, after 16 h at room temperature the reaction mixture is washed with 100 ml water. The organic phase is extracted successively with 100 ml 10% NaHCO3 solution, 100 ml 10% citric acid and 100 ml water. The organic phase is dried over sodium sulfate and the solvent removed under water pump vacuum. The solid crude product (6.3 g) is recrystallized from 35 ml 2-propanol.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
A solution containing the product from Example 10B (1.33 g, 3.68 mmol) in dichloromethane (20 mL) was treated with trifluoracetic acid (20 mL), stirred at 25° C. for 2 hours and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 0-100% acetonitrile/water (0.1% TFA) to give the title compound (1.44 g, 94% yield) as the trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[C:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[NH:23][N:22]=2)[CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:30][C:26]1[CH:25]=[C:24]2[C:29]([C:21](/[CH:20]=[CH:19]/[C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[N:22][NH:23]2)=[CH:28][CH:27]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Product: COc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4cccnc4)n[nH]c3c1)C(=O)N2
Yield: 67.2 %

Procedure:
The title compound (53 mg, 67%) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 5-methyoxyoxindole (32.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 4:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.50 (br. s, 1H, NH), 10.44 (s, 1H, NH), 8.91 (d, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.73 (d, J=16.8 Hz, 1H), 7.59 (d, J=16.4 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.0 Hz, 5.2 Hz, 1H), 7.19 (d, 1H), 6.86 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 3.78 (s, 3H); MS ESI 395.2 [M+H]+, calcd for [C24H18N4O2+H]+ 395.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:5]1[S:1][C:2]2[CH:8]=[C:7]([Sn:15]([CH3:17])([CH3:16])[CH3:14])[S:6][C:3]=2[CH:4]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2sccc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2sc([Sn](C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of thieno[3,2-b]thiophene (see Fuller et al., J. Chem. Soc. Perkin Trans. 1997, 1, 3465-70) (2.00 g, 14 mmol) is dissolved in anhydrous THF (100 ml) and cooled to −78° C. under nitrogen. A solution of n-butyllithium (12 ml of a 2.5M solution in hexanes, 30 mmol) is added dropwise over 5 min, and the resulting solution is allowed to warm to 20° C. over 30 min and stirred at that temperature for 3 h. The resulting suspension is cooled to −78° C. and trimethyltin chloride (5.9 g, 30 mmol) is added at once as a solid. The reaction is allowed to warm to RT over 4 h and stirred at that temperature for an additional 20 h. The reaction is quenched by the addition of saturated sodium hydrogen carbonate (100 ml). Ethyl acetate (50 ml) is added and the layers separated. The organic layer is washed with sodium carbonate (80 ml of a 2M aqueous solution) and brine (80 ml), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product is dry loaded onto a 20 g reverse phase silica column and eluted with acetonitrile. The first fraction is collected, concentrated and recrystallised from acetonitrile to afford the product as white flakes. M/Z cluster centred at 466 (M+). Found C, 30.9; H, 4.4. Calc. for C12H20S2Sn2C, 30.9; H, 4.3. 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 2H), 0.39 (s, 18H). 13C NMR (75 MHz, CDCl3) δ 147.5, 141.2, 126.1, −8.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)C.[OH-].[Na+]>[C:12]([C:11](=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:13]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1ccc(CC#N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C#N)=Cc2ccc(Cl)cc2)cc1OC
Yield: 79.7 %

Procedure:
A mixture of 3,4-dimethyoxyphenylacetonitrile (1.77 g, 10.0 mmol, purchased from Tokyo Kasei,) and 4-chlorobenzaldehyde (1.4 g, 10.0 mmol, purchased from Tokyo Kasei) in 5 ml of ethanol was heated to dissolve. Two drops of 20% aqueous sodium hydroxide solution was then added and the reaction mixture was stirred over night. The resultant reaction mass was crushed in ethanol. The precipitate was Collected and washed with ethanol then with hexane, and dried to give 2.39 g (yield: 79.7%) of α-cyano-3,4-dimethoxy-4'-chlorostilbene as a greenish yellow crystalline.
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:13].N([O-])=O.[Na+].[BrH:18]>>[Br:18][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Cl)c(Br)c(Cl)c1

Procedure:
Methyl 4-amino-3,5-dichlorobenzoate (32 g.) dissolved in 48% hydrobromic acid (100 ml.) was cooled to 0° and sodium nitrite (10.5 g.) was added. The solution was added slowly to a mixture of 48% hydrobromic acid (80 ml.) and cuprous bromide (35 g.) and the mixture heated at reflux for 2 hours. After cooling, the mixture was extracted with ethyl acetate and the organic extracts washed with brine, dried (anhydrous magnesium sulphate) and evaporated to give a dark solid. Crystallisation from ethyl acetate gave methyl 4-bromo-3,5-dichlorobenzoate (20 g.). Nuclear Magnetic Resonance Spectrum (NMR) was as follows: 1H: 4.0,3H,s; 7.9,2H,s.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH:20]([NH2:23])([CH3:22])[CH3:21]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH:23][CH:20]([CH3:22])[CH3:21]
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Reactant: CC(C)N
Solvent: CO
Product: CC(C)Nc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 82 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine (314 mg), 296 mg of isopropylamine and 25 ml of methanol were treated in the same manner as Example 2 and recrystallized from aqueous ethanol to obtain 276 mg (yield 79%) of 9-(2,6-dichlorobenzyl)-6-isopropylaminopurine as colorless needles melting at 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=C(OC)C=2)=CC=1)[C:29](OC)=[O:30]>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:30][CH3:29])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2cccc(OC)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(OC)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-2-methoxy-6-(3-methoxyphenylthiomethyl)benzoate (Intermediate 105).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[O:12][N:11]=2)=[CH:6][CH:5]=1.N1C=CC=CC=1.F[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:32]([C:31]4[CH:35]=[CH:36][CH:28]=[CH:29][CH:30]=4)=[O:33])[CH2:16]3)[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2noc(C3CCCNC3)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-c2noc(C3CCCN(C(=O)c4ccccc4)C3)n2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
To a mixture of 3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (0.320 g, 1.08 mmol) in THF (2.3 ml, 0.5M) was added Pyridine (0.3 ml, 3.78 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (0.172 g-0.87 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/MeOH: 99/1) to afford 0.26 mg (66%) of {3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-phenyl-methanone as a white powder.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][Br:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)n1ccc2cc(CBr)ccc21
Yield: 76.2 %

Procedure:
A suspension of the product of Step A (5.5 g 23.4 mmol) in 10 mL of CCl4 was heated to reflux. N-bromosuccinimide (4.6 g, 25.7 mmol) and several crystals (approximately 100 mg) of azoisobutyronitrile (AIBN) were added. The resultant solution was stirred at reflux for 4 hours. The solution was cooled, diluted with 1.5 L of CH2Cl2 and washed with 400 mL of H2O and 400 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated to a brown oil. The resultant oil was flash chromatographed eluting with 10:1 hexane/ethyl acetate to afford the titled compound (5.6g, 80%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31]C1C=CC=CC=1N=C=O.Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:31])[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1Cl

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2-chlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 223°-227° C.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:23][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][C:11]=1[CH2:10][C:9]1[CH:24]=[CH:25][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:7][CH:8]=1)[C:16](=[O:17])[N:32]([CH:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)[CH2:21]2
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N(C1CCOCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.10 g), tetrahydro-2H-pyran-4-amine (0.03 g) and anhydrous magnesium sulfate (0.07 g) in THF (2.00 mL) was stirred at room temperature for 1 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.00 mL) and THF (2.00 mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).