Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:23]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33].ClC([O-])=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:23]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CCC(=C2c3ccc(Cl)cc3C=Cc3cccnc32)CC1
Agent: O=C([O-])Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(=C2c3ccc(Cl)cc3C=Cc3cccnc32)CC1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
To a mixture of 755 mg (2.34 mmole) of 8-chloro-11-(1-methyl-4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.5 mL of triethylamine in 25 mL of dry toluene at room temperature and under a nitrogen atmosphere was added 650 μL (4.72 mmole) of 2,2,2-trichloroethyl chloroformate. The mixture was then heated to 90° C. Additional amounts of the chloroformate (500 μL and 300 μL) and triethylamine (1.0 mL each time) were added to the mixture after 2 hr. and 3 hr. 40 min., respectively. After a total reaction time of 5 hr. the mixture was poured into water and extracted three times with CH2Cl2. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography [11/2% MeOH in CH2Cl2 ] to afford 639 mg (56%) of the title compound as a glass.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:50][CH:51]1[CH2:54][NH:53][CH2:52]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:29][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[N:13]=[C:12]([C:8]4[CH:9]=[C:10]([CH3:11])[N:6]([CH2:5][C:4]5[CH:3]=[C:2]([N:53]6[CH2:54][CH:51]([OH:50])[CH2:52]6)[CH:32]=[CH:31][CH:30]=5)[N:7]=4)[O:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(F)CCOCC4)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C4(F)CCOCC4)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.302 mmol) of the compound from Example 5A and 141 mg (0.452 mmol) of the compound from Example 8A were used to obtain 62 mg (42% of theory) of the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[C:29](O)(=[O:38])/[CH:30]=[CH:31]/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:38])/[CH:30]=[CH:31]/[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccccc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-cinnamic acid, by the method of Example 1, step K, giving a solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H36N4O2: 484 (M+H). Found: 484
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].Cl>C(#N)C>[C:22]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])[CH2:23][CH3:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)CC)C(=O)OCC
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To magnesium chloride (2.96 g, 31.2 mmol) was added dry acetonitrile (5 mL) and the mixture was then cooled in ice and treated with diethyl malonate (5 g, 31.2 mmol). Once the mixture was cold, triethylamine (8.6 mL, 62.5 mmol) was added and the resulting suspension was stirred for 15 min. Propionyl chloride (2.71 mL, 31.2 mmol) was added dropwise and the mixture was stirred at 0° C. for 1.5 h and at ambient temperature for 5 h. The mixture was cooled in an ice-bath and treated with aqueous hydrochloric acid (2M, 10 mL) and the product extracted with ether. The organic phase was washed with water then brine, dried and concentrated to afford 6.31 g of a yellow oil. This was dissolved in ether and washed with aqueous hydrochloric acid (2M) then brine, dried and concentrated to afford 5.93 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([S:7](=[O:10])(=[O:9])[NH2:8])[S:4][C:3]=1[CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15].Cl[C:18](OC1C=CC=CC=1)=[O:19].C(N(CC)CC)C.[Br:34][C:35]1[S:39][C:38]([NH2:40])=[N:37][C:36]=1[CH3:41]>C(#N)C>[C:14]([O:13][CH2:12][CH2:11][C:3]1[S:4][C:5]([S:7]([NH:8][C:18](=[O:19])[NH:40][C:38]2[S:39][C:35]([Br:34])=[C:36]([CH3:41])[N:37]=2)(=[O:10])=[O:9])=[CH:6][C:2]=1[CH3:1])(=[O:16])[CH3:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)OCCc1sc(S(N)(=O)=O)cc1C
Reactant: Cc1nc(N)sc1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1sc(S(=O)(=O)NC(=O)Nc2nc(C)c(Br)s2)cc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
Acetic acid 2-(3-methyl-5-sulfamoyl-thiophen-2-yl)-ethyl ester (0.120 g, 0.456 mmol) was dissolved in 4.5 mL of abs. acetonitrile and treated successively with phenyl chloroformate (0.057 g, 1.00 eq.) and triethylamine (0.159 mL, 2.5 eq.), and the mixture kept at ambient temperature for 1 h. 5-Bromo-4-methyl-thiazol-2-ylamine (0.088 g, 1.00 eq.), dissolved in a tiny amount of acetonitrile, was then added, and the mixture heated to 60° C. over night. Cooling, pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate, washing with brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, ethyl acetate/5% MeOH), followed by crystallization from ethyl acetate/heptane, yielded finally 0.089 g of the title compound as light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Nc3cc(N)cc(-c4cnc(C5(O)CCC5)s4)c3)n2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
At 0° C., the product from Step 3 (40 mg, 0.074 mmol) in DCM (0.4 mL) was added to acetyl chloride (6.34 μL, 0.089 mmol) and triethylamine (15.53 μL, 0.111 mmol) and the reaction was aged for 1 h. The mixture was then purified directly by column chromatography on silica gel (30-100%, ethyl acetate: 10:1 methanol in hexanes) to afford tert-butyl 4-{[2-({3-(acetylamino)-5-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (28 mg, 65% yield). Example 109(1). MS ESI: [M+H]+ m/z 581.3. 1H NMR (600 MHz, CDCl3): δ 8.10 (d, J=6.0 Hz, 1H); 7.90 (s, 1H); 7.76 (s, 1H); 7.65 (br s, 1H); 7.53 (s, 1H); 7.11 (s, 1H); 6.14 (d, J=6.0 Hz, 1H); 5.25 (m, 1H); 3.67 (m, 2H); 3.12 (br s, 2H); 2.64 (m, 2H); 2.43 (m, 2H); 2.13 (s, 3H); 1.92 (m, 4H); 1.66 (m, 2H); 1.43 (s, 9H). rhSYK activity=++
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(NC(=O)C(C)C)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
N-(3-hydroxy-4-methyl-phenyl)-isobutyramide (6.48 g, 33.5 mmol) was dissolved in 40 mL of acetone, potassium carbonate (13.9 g, 100.5 mmol) was added followed by methyl iodide (14.3 g, 100.5 mmol). The mixture was stirred at room temperature for about 3 days. The solution was filtered and evaporated under reduced pressure to give 6.6 g of N-(3-methoxy-4-methyl-phenyl)-isobutyramide (95%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.26 (d, J=7.03 Hz, 6 H), 2.17 (s, 3 H), 2.49 (m, 1 H), 3.83 (s, 3 H), 6.71 (dd, J=2.05 Hz, 8.21 Hz, 1 H), 7.02 (d, J=7.91 Hz, 1 H), 7.11 (bs, 1 H), 7.47 (d, J=1.76 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])NC(CC1C=C(F)C=C(F)C=1)C(O)CNC1(C2C=CC=C(C#C)C=2)CC1)([CH3:4])([CH3:3])[CH3:2].Cl.CO.O1CCO[CH2:39][CH2:38]1>>[C:6]([C:38]#[CH:39])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:33]
Reactant: C#Cc1cccc(C2(NCC(O)C(Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)CC2)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: C#CC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
[1-(3,5-difluorobenzyl)-3-[1-(3-ethynylphenyl)cyclopropylamino]-2-hydroxypropyl]-carbamic acid tert-butyl ester (2.34 g, 5.13 mmol) was treated with 4N HCl in dioxane (15.8 mL, 63.3. mmol). The resulting heterogeneous mixture was treated with methanol (10 mL) whereupon it became homogeneous over 30 min. The volatiles were evaporated in vacuo. Dioxane (20 mL) was added and the mixture was evaporated in vacuo to produce a white solid (2.33 g, 106%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-:13].[K+].[K+].[Si:18]([O:25][CH2:26][CH2:27][CH2:28]Br)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([O:13][CH2:28][CH2:27][CH2:26][O:25][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(OCCCO[Si](C)(C)C(C)(C)C)n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 1.96 g of 5-methylpyrazole-3-carboxylic acid ethyl ester in 40 ml of DMF, 2.64 g of potassium carbonate and 3.53 ml of 3-(tert-butyldimethylsilyloxy)propylbromide were added, and the mixture was stirred at 50° C. for 18 hours. The solvent was evaporated, EtOAc was added to the residue, and the organic layer was washed with water and brine and dried over sodium sulfate. After the evaporation of the solvent, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=15:1˜5:1) to obtain 1.39 g of 1-[3-(tert-butyldimethylsilyloxy)propoxyl]-5-methylpyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=O.[CH2:13]([NH:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:19]([N:18]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:10]([C:2]1[CH:3]=[CH:4][C:5]([C:7]([N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[O:9])=[CH:6][N:1]=1)=[O:12])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: CC(C)CCNCCC(C)C
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc(C(=O)N(CCC(C)C)CCC(C)C)nc1

Procedure:
N,N,N',N'-tetraisoamyl pyridine-2,5-dicarboxamide was prepared using the method of Example 1 from pyridine-2,5-dicarboxylic acid and diisoamylamine. The crude product in toluene solution was washed several times with 0.5M aqueous sodium hydroxide and then with 0.5M aqueous hydrochloric acid and water. The solution was then treated with charcoal and filtered. The solvent was distilled under reduced pressure, but the product, a brown oil, was not itself distilled. It was made up as a 0.2M solution in AROMASOL H and tested for extraction of copper in the presence of chloride ion using the method of Examples 6 and 7 except that AROMASOL H was used as solvent. The results are given in Table 3. The results indicate that this is a very weak extractant suitable for recovering copper from aqueous solution of high chloride ion concentrations.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:18]=[CH:17][S:16][C:15]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>>[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:18]=[CH:17][S:16][C:15]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1sccc1NS(=O)(=O)CCc1ccc(Br)cc1
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1ccc(CCS(=O)(=O)Nc2ccsc2S(N)(=O)=O)cc1
Yield: 18 %

Procedure:
The title compound was synthesized as described for Example 210 in 18% yield, starting from 3-[2-(4-bromo-phenyl)-ethanesulfonylamino]-thiophene-2-sulfonic acid amide and 3,3-dimethyl-1-butyne. Purification by column chromatography, using 50% ethyl acetate in hexanes as the eluent, followed by purification by preparative HPLC.
Reaction SMILES: C([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([Cl:10])=[O:9])[CH2:6][CH2:5]1)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[ClH:10].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:8]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:12][CH2:11]2)=[O:9])=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl
Product: O=C(c1ccc(Cl)cc1)C1CCNCC1

Procedure:
By following the manipulative procedures described above in Example 1(c), and (d), 37.4 g of 1-acetylisonipecotoyl chloride, [Example 1(b)] and 40 g of aluminum chloride in 90 ml of chlorobenzene are reacted to produce 4-(4-chlorobenzoyl)piperidine hydrochloride, The salt is recrystallized thrice from an ethanol-ether mixture to give a white product, mp 233°-235° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCc1ccc(Cl)cc1
Product: N=C(OCc1ccc(Cl)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and p-chlorobenzyl alcohol, there is obtained p-chlorobenzyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 103°-105° C.;
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([C:26]2([CH2:29][NH2:30])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([C:26]2([CH2:29][NH:30][C:5]3[C:4]4[N:8]=[CH:9][N:10]([C:3]=4[N:2]=[CH:1][N:6]=3)[C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[CH2:27][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCC1(c2ccccc2)CC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccccc5)CC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 77.5 %

Procedure:
A mixture of 6-chloropurine riboside (8.61 g, 30 mmol), (1-phenylcyclopropyl)methylamine (4.41 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) are refluxed in stirring ethanol (300 mL) under N2 for 20 h. On cooling to 0° the product crystallized. Vacuum filtration and drying in vacuo gives N6-((1-phenylcyclopropyl)methyl)adenosine (9.24 g, 79%) as a very pale khaki solid m.p. 118°-23° C. Found: C, 59.58; H, 5.77; N, 17.49%. C20H23N5O4 calculated requires: C, 60.45; H, 5.79; N, 17.63%.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].C(=O)([O-])[O-:21].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21]
Reactant: CCOC(=O)c1ccc(C#N)c(NC2CCCC2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C(N)=O)c(NC2CCCC2)c1
Temperature: 25 °C
Yield: 334.7 %

Procedure:
A solution of ethyl 4-cyano-3-(cyclopentylamino)benzoate (363 mg, 1.41 mmol), potassium carbonate (50 mg, 0.36 mmol), and 30% aqueous hydrogen peroxide (0.25 mL) in DMSO (1.5 mL) was stirred at 60° C. for 1 h. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated to give ethyl 4-(aminocarbonyl)-3-(cyclopentylamino)benzoate (333 mg, 86% yield). MS (EI) for C15H20N2O3: 277 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ccnc(C(F)(F)F)c3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (274 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (290 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH:18]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:11]=1[CH:15]([CH3:16])[CH3:17])=[O:19]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Reactant: BrCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3cccnc3)c2c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 1.00 g, 3.86 mmol) in DMF (50 ml) was added NaH (463 mg, 19.3 mmol) and and 3-(bromomethyl)pyridine (2.62 g, 15.4 mmol). The reaction was stirred at 60° C. for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→70% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[Cl:17])=[O:8])=[CH:5][CH:4]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N-:48]=[N+:49]=[N-:50].CN(C)C(=[NH2+])N(C)C>C(Cl)(Cl)(Cl)Cl>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][N:48]=[N+:49]=[N-:50])=[CH:11][C:10]=2[Cl:17])=[O:8])=[CH:18][CH:19]=1.[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:10]([Cl:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH2:15][N:48]=[N+:49]=[N-:50])=[O:8])=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(C(=O)c2ccc(C(F)(F)F)cc2)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CN=[N+]=[N-])cc(Cl)c1C(=O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(Cl)c(C(=O)c2ccc(C(F)(F)F)cc2)c(CN=[N+]=[N-])c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 17 %
Yield: 22 %

Procedure:
A stirred mixture of 1-(4-trifluoromethylbenzoyl)-2-chloro-4,6-dimethylbenzene (6.90 g, 22.1 mmol), N-bromosuccinimide (3.94 g, 22.1 mmol), and dibenzoyl peroxide (224 mg, 0.925 mmol) in dry carbon tetrachloride (180 ml) was refluxed 44 hours. Additional N-bromosuccinimide (1.97 g, 11.1 mmol) was added and the mixture was refluxed 24 hours. The mixture was cooled to 0° C., filtered, and washed with carbon tetrachloride. The combined filtrate and washes were evaporated to dryness under vacuum, and the residue was dissolved in dichloromethane (135 ml), treated with tetramethylguanidinium azide (7.25 g, 45.8 mmol), and stirred 40 minutes at ambient temperature. Solvent was removed under vacuum and the residue was stirred with diethyl ether (180 ml). The mixture was filtered and the precipitate was washed with diethyl ether. The combined filtrate and washes were washed twice with water and once with brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum. The residue was dissolved in hexane (300 ml) and decanted, and the residual gum was washed with hexane. The combined hexane layers were evaporated to dryness under vacuum. The residue was chromatographed on silica gel (500 g) eluted with 93:7 (v/v) hexane-ethyl acetate using a preparative high-performance liquid chromatograph to provide 1.71 g (22%) oily 4-(4-trifluoromethylbenzoyl)-3-chloro-5-methylbenzyl azide (A), 1.30 g (17%) 2-(4-trifluoromethylbenzoyl)-3-chloro-5-methylbenzyl azide (B), and 0.48 g of a mixture of A and B.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[NH:18][C:17]2[C:12](=[CH:13][C:14]([Br:19])=[CH:15][CH:16]=2)[C:8]=1[CH2:9][CH2:10][NH2:11])=[O:6])C.C(O)C.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:14]1[CH:13]=[C:12]2[C:17]([NH:18][C:7]([C:5]([OH:6])=[O:4])=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Yield: 91 %

Procedure:
1.00 g. (2.87 mmoles) of ethyl-5-bromo-tryptamine-2-carboxylate hydrochloride are boiled for 2 hours in a mixture of 10 ml. of ethanol and 10 ml. of 4 n aqueous sodium hydroxide solution. The mixture is cooled with ice, acidified to pH 6 with glacial acetic acid, and the separated crystals are collected by filtration. 0.75 g. (91%) of 5-bromo-tryptamine-2-carboxylic acid are obtained; m.p.: 248°-249° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.CO[C:14]1[CH:19]=[C:18]([O:20][CH2:21]C)[CH:17]=[CH:16][C:15]=1O.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:25]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:21][O:20][C:18]1[CH:19]=[CH:14][CH:15]=[CH:16][C:17]=1[CH2:24][CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOc1ccc(O)c(OC)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CCOc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
1.1 g of 4-hydroxybenzotrifluoride and 1.0 g of 2-methoxyphenetyl alcohol were dissolved in 200 ml tetrahydrofuran. 2.6 g of triphenyl phosphine and 2.0 g of diisopropyl azodicarboxylate were added thereto, followed by stirring at room temperature for 24 hours. After evaporating the solvent, the residue was subjected to silica gel column chromatography, to give 1.6 g of 1-methoxy-2-{2-[4-(trifluoromethyl)phenoxy]ethyl}benzene was obtained from fractions eluted with hexane-ethyl acetate (10:1).