Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]([O:18]CC)(=O)[CH2:11][C:12]([O:14]CC)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:14])[CH2:11][C:10]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1C
Reactant: CCOC(=O)CC(=O)OCC
Product: Cc1ccc(NC(=O)CC(=O)Nc2ccc(C)c(C)c2)cc1C
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol 3,4-dimethylaniline and 50 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly (100 mmol≡6.6 mL) on a stream of nitrogen. N1,N3-di(3,4-dimethylphenyl)malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 13.9 g N1,N3-di(3,4-dimethylphenyl)malonamide was obtained (yield 89.6%, purity 98.5%)
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][O:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:3]1.[CH2:19]([Li])[CH2:20][CH2:21]C.BrC(C)C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:18])[CH2:6][O:5][C:4]([CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:20]([CH3:21])[CH3:19])=[N:3]1
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCC1=NC(C)(C)CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)Br
Solvent: C1CCOC1
Product: CCCCCCCCCCC(C1=NC(C)(C)CO1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
A solution of 25.34 g (100 mmoles) of 4,4-dimethyl-2-undecyl-2-oxazoline in 250 ml of dry THF under nitrogen atmosphere was cooled to -78° C. To this was added 62.5 ml (100 mmoles) of 1.6M solution of n-butyl lithium in hexane over a period of 15 minutes and the solution was further stirred for 2 hours. 18.45 g (150 mmoles) of 2-bromopropane was added at -78° C. over a period of 30 minutes and the resulting solution was allowed to warm to room temperature overnight. The solution was poured into 250 ml of saturated ammonium chloride solution and the organic phase was separated. The aqueous phase was extracted with 2×100 ml of ether, the organic phases were combined and extracted with 2×200 ml of brine. After drying over anhydrous magnesium sulphate, the solution was concentrated and the residue was distilled at reduced pressure 10.2 g of starting material was recovered. 8.82 g (50% based on recovered starting material) of product distilled at 131°-134° C./ 0.8 mm Hg. 2.98 g (14.8%) of disubstituted product was obtained as a higher boiling fraction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].N[C@H](C(O)=O)C.B(O)(O)O.[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:34][C:35]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[C@H](N)C(=O)O
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
77 g of 3-(3,4-dihydroxyphenyl)-L-alanine is added with stirring in an argon atmosphere to a suspension of 140 g of borax in 700 ml of water. The mixture is stirred for 15 minutes and then brought to pH 9 (pH meter) with 2-N aqueous sodium hydroxide. A boric acid complex forms in which the hydroxyl groups on the phenyl ring of the alanine derivative are esterified with boric acid. 77 g of chloroformic acid benzyl ester is subsequently added in portions of about 4 ml in the course of three hours at a temperature between 0°C. and 10°C., the pH of the mixture being held between 9 and 9.5 by the addition of 2-N sodium hydroxide. After the addition, the mixture is cooled to 0°C. and filtered off from a small amount of undissolved material, and the filtrate is extracted twice with 500 ml of diethyl ether each time. The ether extracts are washed once with 100 ml of water and then discarded. The aqueous alkaline extracts are brought to pH 1 with 6-N aqueous sulphuric acid with ice-cooling and then extracted twice with 1,000 ml of diethyl ether each time. The organic extracts are washed four times with 500 ml of water each time, then combined and, after drying over sodium sulphate and animal charcoal, evaporated under vacuum with the addition of toluene. 125.7 g of crude N-benzyloxycarbonyl-3-(3,4-dihydroxyphenyl)-L-alanine is thus obtained as a weakly violet-colored glass; [α]D25 = +1.5°(c = 1.935%, methanol).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]2.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:44][CH:45]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]([CH2:55][CH2:56][CH2:57][O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[C:46]1=[O:66]>C(Cl)Cl>[Si:59]([O:58][CH2:57][CH2:56][CH2:55][N:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:54][CH:45]([NH:44][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=3)=[O:23])[C:46]1=[O:66])([C:62]([CH3:64])([CH3:65])[CH3:63])([CH3:61])[CH3:60]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C(=O)C(N)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Yield: 82.3 %

Procedure:
Prepared exactly as in Method 7 using HOBT (174 mg, 1.3 mmol), 5-chloroindole-2-carboxylic acid (250 mg, 1.3 mmol), DIPEA (0.22 mL, 1.3 mmol), EDCI (308 mg, 1.6 mmol) and 3-amino-1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3,4-dihydroquinolin-2(1H)-one (Method 14, 432 mg, 1.3 mmol) in DCM (10 mL). This gave the title compound (548 mg, 82%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH:7]2[S:11][C:10]3[C:12]([Cl:19])=[C:13]([Cl:18])[C:14]([O:16][CH3:17])=[CH:15][C:9]=3[CH:8]2O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:18][C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:9]2[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:11][C:10]=2[C:12]=1[Cl:19]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C1CCCCC1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 1 h
Yield: 64.7 %

Procedure:
A mixture of 14.7 g of 2-cyclohexyl-6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxybenzo[b]thiophene, 90 ml of glacial acetic acid and 21 ml of boron trifluoride etherate is warmed on a steam bath until it becomes homogeneous and then stirred for one hour. To the reaction mixture is added 100 ml of cold 10% sodium hydroxide solution. The mixture is further basified with 50% sodium hydroxide solution and extracted with three 230 ml-portions of ether. The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated. Recrystallization of the residue from ether-hexane gives 9.0 g of 6,7-dichloro-2-cyclohexyl-5-methoxybenzo[b]thiophene as off-white crystals, mp 60°.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20]([O:22]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:3]1=[O:32].[CH3:33][O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1.C(N(CC)CC)C>C1COCC1>[CH3:33][O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:20]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:32])=[O:22])[CH:38]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92 g, 4.47 mmol) was dissolved in THF (25 ml) and treated with a solution of (3-aminophenyl)acetic acid methyl ester (670 mg, 4.06 mmol) in THF (5 ml) followed by triethylamine (615 mg, 6.09 mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20 ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:1 hexane:ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester. This ester (885mg, 1.94mmol) was dissolved in THF (5 ml) and treated with a solution of lithium hydroxide (815 mg, 19.4 mmol) in water (10 ml). The mixture was stirred at ambient temperature for 3 hours, diluted with water (100 ml), acidified with 1N HCl, and extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried over sodium sulfate, filterate, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with chloroform followed by 9:1 chloroform:methanol. The product fractions were combined and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate to provide the title compound: (mp 167°-170° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:22]([O:27][CH2:28][CH3:29])(=[O:26])[C:23]([CH3:25])=O.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:23]([C:22]([O:27][CH2:28][CH3:29])=[O:26])=[CH:25]2
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc2cccc(Br)c2[nH]1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
11.0 g 2-bromophenylhydrazine and 550 mg p-toluenesulphonic acid monohydrate are dissolved in 200 ml of toluene, combined with 6.74 ml ethyl pyruvate and refluxed for 2 hours using the water separator. The mixture is allowed to cool to 40° C. and combined with a solution that is obtained by dissolving 44.75 g p-toluenesulphonic acid monohydrate in 300 ml of toluene and refluxing for two hours using the water separator. Then the mixture is refluxed for 12 hours using the water separator. After cooling to ambient temperature the solvents are eliminated in vacuo, the residue is taken up in ethyl acetate and washed successively with water and saturated aqueous sodium hydrogen carbonate solution. After drying with magnesium sulphate the mixture is combined with activated charcoal, stirred for 15 minutes and filtered through kieselguhr. The process of adding activated charcoal, stirring and filtering is repeated twice more. The solvents are eliminated in vacuo and the residue is taken up in petroleum ether/dichloromethane 7:3. 30 g of silica gel are added, the mixture is stirred for 10 minutes and then suction filtered through kieselguhr. The suction filtered silica gel is washed with petroleum ether/dichloromethane 7:3. The solvents are eliminated in vacuo.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.Cl.[CH3:14]O>>[CH3:14][O:12][C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CO
Reactant: Oc1cc(O)c2ccccc2c1
Agent: Cl
Product: COc1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a stirring solution of 1,3-dihydroxynaphthalene (2.31 g, 14.4 mmol) in methanol (150 mL) at 0° C., hydrochloride gas was bubbed for 10 min. The resulting solution was continued stirring at room temperature for 24 hrs. A residue was obtained after evaporation of methanol and purified by silica gel column chromatography eluted with chloroform to provide the title compound as purple crystals (1.42 g, 57%). 1H NMR(300 MHz CDCl3) δ8.08(d, 1H), 7.70(d, 1H), 7.46(t, 1H), 7.34(t, 1H), 6.78 (s, 1H), 6.54 (s, 1H), 5.61(s, 1H), 3.90(s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][NH:19][C:20]3[N:25]=[C:24]([NH2:26])[N:23]4[N:27]=[C:28]([C:30]5[O:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:22]4[N:21]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClC1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:28]1[N:29]=[C:22]2[N:21]=[C:20]([NH:19][CH2:18][CH:15]3[CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]5[N:48]=[CH:47][CH:46]=[CH:45][N:44]=5)[CH2:9][CH:10]4[CH2:17][CH2:16]3)[N:25]=[C:24]([NH2:26])[N:23]2[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CNc3nc(N)n4nc(-c5ccco5)nc4n3)CC[C@@H]2C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(NCC2CCC3CN(c4ncccn4)CCN3C2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (1 eq., see Example 7(b) above) in methylene chloride was added trifluoroacetic acid to reach a final concentration of 10% TFA. The mixture was stirred at room temperature for 2 hours, after which the solvent was removed under reduced pressure, and the residue was dissolved in acetonitrile. To the resulting solution was added 2-chloropyrimidine (1 eq.) and Na2CO3 (2 eq.). The mixture was stirred at around 80° C. for overnight. The solvent was removed afterwards, and the residue was purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford (7RS,9aSR)-2-furan-2-yl-N5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=4.7 Hz, 2H), 7.70 (d, J=2 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 6.72 (t, J=4.7 Hz, 1H), 6.62 (dd, J=2, 3.6 Hz, 1H), 4.97 (d, J=14.1 Hz, 2H), 3.34-3.58 (m, 4H), 3.11-3.24 (m, 3H), 2.82-3.03 (m, 2H), 2.33 (m, 1H), 2.10 (d, J=14.1 Hz, 1H), 2.02 (d, J=13.2 Hz, 1H), 1.60-1.69 (m, 1H), 1.39-1.49 (m, 1H). MS m/z: 448[M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-])=O.N[C:12]1[CH:17]=CC=[CH:14][CH:13]=1.C(N1CCCC1=O)O.ClCC(Cl)=O>>[CH2:17]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])[CH2:12][CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccccc1S
Reactant: Nc1ccccc1
Agent: O=C(Cl)CCl
Agent: O=C1CCCN1CO
Product: CCCCSc1ccccc1N

Procedure:
2-Butylmercaptoaniline was prepared from -2-nitrothiophenol by a two-step reaction sequence consisting of alkylation followed by reduction corresponding to the procedure described in Example 4. The aniline then was condensed with N-methylolpyrrolidone, followed by reaction with chloroacetyl chloride to yield the desired product.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:20]([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:22])[NH:4][CH2:3]1>O1CCOCC1.O>[CH3:1][C@H:2]1[C@H:20]([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:22])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)[C@H](C)CNC3=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)cc3n2[C@H]1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.5 %

Procedure:
A mixture of ethyl trans-4,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (363 mg, 1.2 mmol) and LiOH monohydrate (76 mg, 1.8 mmol) in dioxane:water (1:1, 10 mL) is stirred at room temperature for 6 h. The solvents are removed and water is added. The solution is acidified to pH 5 with 1M HCl and the resulting white solid is filtered and dried to afford the title compound (201 mg, 61%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2)=O.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[N:21]1([CH2:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Reaction time: 8 h

Procedure:
In 100 mL of 1,2-dichloroethane, 5.0 g (18 mmol) of (R)-tert-butyl 6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate and 3.1 g (36 mmol) of piperidine were combined. Next, 7.6 g (36 mmol) of sodium triacetoxy borohydride was added and the mix was stirred under nitrogen overnight. The mix was then dissolved in 100 mL of ethyl acetate, washed with 25 mL of saturated sodium bicarbonate, washed with 25 mL of brine, dried with sodium sulfate and concentrated to yield the crude material.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1.[CH3:20][C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:24])[CH:22]=[O:23].[NH4+].[Cl-]>C1COCC1.O>[F:17][C:16]([F:19])([F:18])[C:8]1[CH:7]=[C:6]([CH:22]([OH:23])[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:24])[CH3:20])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Reactant: CC(C)(C=O)NC(=O)OCc1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NC(=O)OCc1ccccc1)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature under N2 and the reaction was stirred for 30 min. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and the reaction was allowed to warm to room temperature over 3 h. Saturated NH4Cl (10 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: NC1C=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:45](=[O:46])[C:33]3=[CH:34][NH:35][C:36]4[CH:37]=[CH:38][C:39]([N+:42]([O-])=O)=[CH:40][C:41]=4[C:32]3=[N:31]2)=[CH:26][CH:25]=1>>[NH2:42][C:39]1[CH:38]=[CH:37][C:36]2[NH:35][CH:34]=[C:33]3[C:45](=[O:46])[N:30]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=4)[N:31]=[C:32]3[C:41]=2[CH:40]=1
Reactant: COc1ccc(-n2nc3c4cc([N+](=O)[O-])ccc4[nH]cc-3c2=O)cc1
Agent: Nc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Product: COc1ccc(-n2nc3c4cc(N)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 6a using 5c. 1H-NMR (DMSO-d6) δ (ppm): 3.77 (3H, s), 6.75 (1H, dd, J=8.91, 2.37 Hz), 6.90 (2H, m), 7.10 (1H, d, J=2.08 Hz), 7.44 (1H, d, J=8.91 Hz), 8.05 (2H, m), 8.39 (1H, d, J=6.53 Hz). m/z 307.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+].[Cl-].O>O1CCOCC1.CCO.[Fe]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc([N+](=O)[O-])c1)cn2C1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Fe (8.24 g, 147.55 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitro-phenyl)methanone (10.37 g, 29.51 mmol) and NH4Cl (6.31 g, 118.0 mmol) in 1,4-Dioxane (200 mL), EtOH (150 mL), and water (100 mL). The resulting suspension was heated to reflux for 2 h, at this time the reaction was cooled to room temperature then filtered through celite eluting with EtOAc. The filtrate was dried over MgSO4 and concentrated to afford the title compound as a yellow solid (9.48 g, 100%). MS: 322.3 (MH+); HPLC Rf: 4.55 min. (HPLC method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:10]([NH2:16])=[N:11][C:12]([NH2:15])=[CH:13][CH:14]=1.N1C(C)=CC=CC=1C.[O:25]1[N:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1>>[NH2:16][C:10]1[N:11]=[C:12]([NH:15][C:30]([C:27]2[CH:28]=[N:29][O:25][N:26]=2)=[O:31])[CH:13]=[CH:14][C:9]=1[C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)c1cnon1
Reactant: Nc1ccc(-c2cc(Cl)ccc2Cl)c(N)n1
Solvent: Cc1cccc(C)n1
Product: Nc1nc(NC(=O)c2cnon2)ccc1-c1cc(Cl)ccc1Cl

Procedure:
N-[6-Amino-5-(2,5-dichlorophenyl)pyridin-2-yl]-1,2,5-oxadiazole-3-carboxamide was prepared by a method analogous to Method A, as described for Example 1 above, using 3-(2,5-dichlorophenyl)pyridine-2,6-diamine (Preparation 7), 1 equivalent lutidine and 1 equivalent acid chloride prepared from 1,2,5-oxadiazole-3-carboxylic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O.[Cu].[Cu](Br)Br>[C:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1I
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Agent: Br[Cu]Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1N(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
In 20 ml of nitrobenzene were refluxed 2.27 g of N-acetyl-2-phenoxyaniline, 1.3 ml of 2-iodoanisole, 1.38 g of potassium carbonate, 133 mg of a copper powder and 200 mg of copper bromide under heating for 8 hours. The reaction solution was cooled to room temperature, and after addition of ethyl acetate, the insoluble matter was removed by filtration. The filtrate was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:4) to give 660 mg of N-acetyl-N-(2-methoxyphenyl)-2-phenoxyaniline as an oil.