Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3](C)=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:13]C1C=CC(C(O)=O)=C(C)C=1>>[Cl:13][C:3]1[C:2]([I:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: Cc1cc(Cl)ccc1C(=O)O
Product: Cc1cc(Cl)c(I)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 2.1, except 4-chloro-2-methylbenzoic acid was used in place of 2,4-dimethylbenzoic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)(C)C>[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[C:2]2[C:3]3[CH:11]=[CH:10][N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc2c(c1C)NCC2
Reactant: Clc1ncnc2cnccc12
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1ccc2c(c1C)N(c1ncnc3cnccc13)CC2
Yield: 17.9 %

Procedure:
To 4-chloro-pyrido[3,4-d]pyrimidine (200 mg, 1.21 mmol) in isopropanol (3 mL) was added 6,7-dimethylindoline (211 mg, 1.44 mmol) and pyridine (190 mg, 2.41 mmol). The mixture was heated to reflux under an atmosphere of dry N2(g) for 6hours. Solvent was removed in vacuo and the residue was dissolved in CHCl3 and washed with saturated aqueous Na2CO3. The organic phase was dried over Na2SO4, concentrated in vacuo, and flash chromatographed on silica in 45% acetone/hexanes to afford 60 mg of 4-(6,7dimethyl-2,3-dihydro-indol-1-yl)-pyrido[3,4-d]pyrimidine (LC-MS: 278 (MH+). This material was dissolved in a minimum volume of 10% MeOH in CH2Cl2, and 1 mole equivalent of HCl in diethyl ether was added dropwise with stirring. The mixture was diluted with diethyl ether (4 volumes) and the precipitated HCl salt of the product was filtered and dried in vacuo (58 mg): MP: 248° C.; GEMS: 277 (M+); anal. RP-HPLC: 4.06 minutes.
Reaction SMILES: [C:1]1([C@H:7]([NH2:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[CH2:13][O:14]CC>CCOCC>[C:1]1([C@H:7]([N:10]=[C:13]=[O:14])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: CCOCC
Agent: Cl
Product: CC[C@@H](N=C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1(R)-phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mL) was added a 1.0 M solution of HCl/Et2O (212 mL, 212 mmol). The mixture was stirred for 30 min, then the crude solution was evaporated to dryness on a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 mL), triphosgene was added (11.67 g, 39.3 mmol) and the resulting suspension was stirred at reflux for 3 h at room temperature overnight. The reaction mixture was concentrated and the final volume adjusted to 200 mL with toluene giving a final concentration of 0.53M. The resulting isocyanate solution was used as such. An aliquot (170 mL) was concentrated to give a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15].Cl.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[O:8][C:14](=[O:15])[NH:10][N:9]=2)[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)o1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-Nitrobenzohydrazide (2.05 g, 11.3 mmol) obtained in Step 1 was dissolved in THF (57 mL), and the mixture was stirred at room temperature for 40 minutes after adding 1,1′-carbonyldiimidazole (2.01 g, 12.4 mmol). The mixture was stirred after adding 6 mol/L hydrochloric acid (40 mL) and water (20 mL), and the precipitated solid was filtered off and dried to give 5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one as a white solid. 5-(3-Nitrophenyl)-1,3,4-oxadiazol-2(3H)-one so obtained was dissolved in DMF (52 mL), and the mixture was stirred at room temperature for 40 minutes after adding potassium carbonate (2.14 g, 15.5 mmol) and methyl iodide (0.77 mL, 12.3 mmol). The mixture was stirred after adding water, and the precipitated solid was filtered off and dried to give 3-methyl-5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (2.17 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][C:31]([NH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1)=[O:32]
Reactant: CN(C)CCCC(=O)O
Reactant: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(N)ccc4c3c2)c1
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(NC(=O)CCCN(C)C)ccc4c3c2)c1

Procedure:
This was similarly prepared from 7-amino-3-(3-methoxyphenyl)-9H-carbazole-1-carboxamide and 4-(dimethylamino)butanoic acid. MS (ESI) m/z 445.26 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.45 (1H, d, J=1.83 Hz), 8.14 (1H, d, J=1.53 Hz), 8.10 (1H, d, J=8.55 Hz), 8.05 (1H, d, J=1.83 Hz), 7.35-7.39 (3H, m), 7.29 (1H, dd, J=8.39, 1.68 Hz), 6.93 (1H, dt, J=7.55, 2.02 Hz), 3.91 (3H, s), 2.54-2.61 (2H, m), 2.50 (2H, t, J=7.32 Hz), 2.40 (6H, s), 1.91-2.02 (2H, m).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[NH:13][C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:6])=[O:5].I[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[N:13]([CH3:29])[C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:5])=[O:6]
Reactant: CI
Reactant: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To the suspension of NaH (60% dispersion in mineral oil, 139 mg, 3.5 mmol) in DMF is added 7-methanesulfonyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (1.15 g, 3.2 mmol), prepared as in Reference 1, at 0° C. When H2 evolution has ceased, iodomethane (0.99 ml, 15.8 mmol) is added and the reaction mixture is stirred for 3 hours at room temperature. The mixture is diluted with ethyl acetate, and washed with 5% aqueous Na2S2O3 solution to remove DMF. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (SiO2, EtOAc/hexane=1/1) to give 7-methanesulfonyl-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.85 g, 70%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([CH2:22][OH:23])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][O:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20]1
Reactant: OCC1CC1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCC1CC1

Procedure:
The title compound, white solid, m.p.=108° C., MS: m/e=309.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and cyclopropyl-methanol.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=O)[C:3]=1[NH2:4].[N:13]#[C:14][NH2:15]>C(O)(=O)C.Cl>[NH2:15][C:14]1[N:13]=[N+:10]([O-:12])[C:5]2[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([Br:1])[C:3]=2[N:4]=1
Reactant: N#CN
Reactant: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(Br)c2nc(N)n[n+]([O-])c2c1
Temperature: 50 °C
Yield: 51.5 %

Procedure:
To 13.0 g (56.3 mmol) of 2-bromo-4-methyl-6-nitroaniline stirring in a mixture of 25 ml glacial acetic acid and 5 ml of concentrated hydrochloric acid at 80° C., 29.0 g (690.5 mmol) of cyanamide and 25 ml of concentrated hydrochloric acid were added simultaneously, separately, and very slowly. At one point during the addition, a vigorous exotherm occurred and the external heat immediately removed. After the addition, the reaction was heated at reflux for 15 minutes. On cooling to about 50° C., 100 ml of 25% aqueous sodium hydroxide were added dropwise and the mixture heated at reflux 15 minutes. The reaction was cooled to room temperature, the insoluble orange solid filtered and washed with water followed by ethyl acetate to afford 7.4 g of yellow 3-amino-5-bromo-7-methyl-1,2,4-benzotriazine-1-oxide after drying.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:23]2[N:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1noc(C)n1
Product: Cc1nc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)no1
Yield: 5 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol to give the titled compound as a brown solid (5.3 mg, 5%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[NH:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1>>[CH:2]1([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=3[CH:10]=[CH:9]2)[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: BrC1C=CCCC1
Product: O=Cc1cccc2c1ccn2C1C=CCCC1
Yield: 17.9 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.44 g of 3-bromocyclohexene and 2.00 g of indole-4-carbaldehyde as a starting material to give 556 mg of 1-(2-cyclohexenyl)indole-4-carbaldehyde as a yellow-colored oily substance. The yield thereof was found to be 18%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:11]([O:14][CH2:15][CH2:16]Cl)(=[O:13])[CH3:12].OP([O-])(O)=O.[Na+]>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][O:3][CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: OCc1ccccn1
Reactant: CC(=O)OCCCl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1ccccn1

Procedure:
0.530 g of sodium hydride is added over 20 minutes at 0° C. to a solution of 1 g of 2-hydroxymethylpyridine and DMF. 1.6 ml of chloroethyl acetate is added at 0° C. 2 ml of a solution of sodium acid phosphate is poured in, then the reaction medium is concentrated under reduced pressure. The product obtained is chromatographed on silica eluting with a methylene chloride methanol mixture 90-10. 4.5 g of product is obtained which is chromatographed on silica eluting with a methylene chloride, methanol mixture 90-10. The product is obtained is purified and 1.30 g of sought product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1C(=O)CCNc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCCNc2ccccc21

Procedure:
1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 18A (1.7 g, 9.65 mmol) was reduced with lithium aluminium hydride according to the procedure in Example 15A; yield 1.34 g (86%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH3:17])[N:11]=1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH3:17])[N:11]=1
Reactant: CNc1nccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nccc(CO)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 269.5 %

Procedure:
4-tert-Butyldimethylsilyloxymethyl-2-methylaminopyrimidine (40 mg, 0.16 mmol, Reference Compound No. 6-1) was dissolved in tetrahydrofuran (3.0 mL), then a solution of tetrabutylammonium fluoride trihydrate (55 mg, 0.17 mmol) in tetrahydrofuran (3.0 mL) was added thereto, and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was suspended into 25% methanol-chloroform solution, and the mixture was filtered with silica gel (2.0 g). The filtrate was concentrated under reduced pressure to give 60 mg of the mixture of the title Reference Compound and tetrabutylammonium fluoride as a brown oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br-:22].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH2:19][Br:22])=[C:13]([CH3:21])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(Oc2ccc3c(c2)OCO3)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
To a solution of 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)ethanone (4.80 g, 16.9 mmol) in acetonitrile (33.8 mL) was added tetrabutylammoniumtribromide (TBABr3, 8.14 g, 16.9 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)-2-bromoethanone (6.70 g), which was used directly for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:42][C:43]1[CH:48]=[C:47]([CH:49]([CH3:52])[CH2:50][NH2:51])[CH:46]=[CH:45][C:44]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:51][CH2:50][CH:49]([C:47]1[CH:46]=[CH:45][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:43]([F:42])[CH:48]=1)[CH3:52])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CC(CN)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Product: CC(CNC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(-c2ccccc2)c(F)c1
Yield: 42.4 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (79 mg, 0.14 mmol) and 2-fluoro-β-methyl-4-biphenylethylamine hydrochloride (45 mg, 0.17 mmol) according to Method C to give the title compound (44 mg). 1H-NMR (400 MHz, CD3OD) d 7.75 (s, 1H), 4.78 (s, 1H), 4.57 (s, 1H), 4.51 (m, 1H), 4.22 (m, 1H), 3.52 (m, 1H), 3.41 (m, 1H), 3.22 (m, 1H), 3.06-2.85 (m, 4H), 2.72 (m, 1H), 1.35 (s, 9H), 1.20 (dd, J=7.0 Hz, J=15.7 Hz, 4H); HRMS m/z 741.3094 (calc. of monoisotopic mass for C41H44FN3O9 gives 741.3062).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][O:6][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
A solution of 3-bromo-5-nitrobenzyl alcohol (5 g, 21.5 mmol), in N,N-dimethylformamide (5 mL) was treated with tert-butyldimethylsilyl chloride (4.9 g, 32.3 mmol) and imidazole (2.5 g, 36.6 mmol) and stirred at room temperature for 14 h. The reaction was quenched with water and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica (0-75% ethyl acetate in hexanes) afforded [(3-bromo-5-nitrobenzyl)oxy](tert-butyl)dimethylsilane (7.32 g, 20.1 mmol, 93% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].Cl[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[Br:1][C:2]1[N:3]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: ClCSc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CSc3ccccc3)c2c1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1.00 g, 2.97 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 139 mg, 3.47 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To this reaction mixture was added chloromethylsulfanylbenzene (0.38 ml, 2.94 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1-7:1) to give methyl 2-bromo-3-cyclohexyl-1-phenylsulfanylmethyl-1H-indole-6-carboxylate (1.10 g, yield 84.0%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH:18]([CH3:21])[CH:19]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(CNCCNC(=O)OC(C)(C)C)c1ccccc1
Yield: 56 %

Procedure:
In the same way as that described in Example 4, Step 1, using tert-butyl-N-(2-aminoethyl)carbamate (1.6 g, 10 mmol), 2-phenylpropionaldehyde (1.32 mL, 10 mmol), MeOH (100 mL), acetic acid (1.72 mL, 30 mmol) and sodium cyanoborohydride (1.26 g, 20 mmol). The crude residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH (90:10), to give the amine (1.56 g, 56%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ1.26 (3H, d, J=6.9 Hz), 1.42 (9H, s), 2.70-2.81 (4H, m), 2.90-3.00 (1H, m), 3.14-3.24 (2H, m), 4.89 (1H, br s), 7.19-7.35 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(Cn2cccc2)cc1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2cccn2Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
In a flask were placed 3.0 ml (22.9 mmol) 3-methylbenzoyl chloride and 50 ml methylene chloride. Then 22.9 ml (1.0M in CH2Cl2, 22.9 mmol) stannic chloride was added dropwise. The contents of the flask were mixed for 5 minutes, then 3.6 g (22.9 mmol) N-benzylpyrrole in 10 ml methylene chloride was added dropwise. The reaction mixture was stirred overnight, then quenched with water, washed with brine, dried and condensed to yield an oil. The oil was purified by flash chromatography with ethyl acetate/hexanes/silica gel, yielding two fractions. These were analyzed spectroscopically; one was found to be the desired 2-benzoyl compound, the other the corresponding 3-benzoyl compound.
Reaction SMILES: Cl.[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][CH3:23])[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[CH2:29](Br)[CH:30]1[O:34][CH2:33][CH2:32][CH2:31]1>ClCCl.CN(C)C=O>[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]([CH3:23])[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][O:34]1)[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: BrCC1CCCO1
Reactant: CN[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CC1CCCO1)[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Reaction time: 20 h
Yield: 31.6 %

Procedure:
A solution of trans-(±)-N-methyl-N-[2-(methylamino)cyclohexyl]benzo[b]thiophene-4-acetamide monohydrochloride (120 mg, 0.34 mmol) in dichloromethane (10 ml) was treated with saturated aqueous sodium bicarbonate to liberate the parent amine. The oil was dissolved in dimethyl formamide and treated with tetrahydrofurfuryl bromide (68 mg, 0.41 mmol) and sodium bicarbonate (43 mg, 0.5 mmol). The resulting mixture was stirred in an oil bath at 95°-110° C. for 20 hours then concentrated in vacuo, poured into saturated aqueous sodium bicarbonate (15 ml) and extracted with dichloromethane (2×15 ml). Silica gel chromatography (70:30:1 ethyl acetate-hexanetriethylamine) furnished trans-(±)-N-methyl-N-(2-(methyl[(tetrahydro-2-furanyl)methyl]amino)cyclohexyl)-benzo[b]thiophene-4-acetamide as a colourless oil (43 mg, 32%); m/e: 400 (M+), 329, 286, 195, 147; t.l.c. analysis of this product (50:50:1 ethyl acetate-hexane-triethylamine, multiple development) indicated that it consisted of two components.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13](O)=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]2[NH:26][C:13]([C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C@H:10]([OH:11])[CH3:12])=[N:27][C:22]=2[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 Steps 1 and 2 using N-Boc-L-threonine (Preparation 52) and 4-tert-butyl-diaminobenzene.