Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:14]1([C:20]2[N:21]=[CH:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][C:41]2=[O:46])[CH:36]=[CH:37][CH:38]=1.[Cl-].[NH4+]>C1CCCCC1.O1CCCC1.C(OCC)C.C(Cl)(Cl)(Cl)Cl>[OH:46][C:41]1([C:22]2[O:23][C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=2)[CH2:42][CH2:43][CH2:44][CH2:45][CH:40]1[CH2:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Reactant: COc1cccc(CC2CCCCC2=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: COc1cccc(CC2CCCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A 1.5 M solution of lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (19.9 ml) was added dropwise to a stirred solution of 4,5-diphenyloxazole (6.0 g) in tetrahydrofuran (36 ml) and diethyl ether (18 ml) under dry ice--carbon tetrachloride cooling and the mixture was stirred at the same temperature for a while and at 0° C. for a while. A solution of 2-[(3-methoxyphenyl)methyl]cyclohexanone (5.92 g) in tetrahydrofuran (16 ml) was added to the reaction mixture under dry ice-acetone cooling, and the resulting mixture was stirred at the same temperature for several hours. Then the reaction temperature was allowed to rise gradually to room temperature and the reaction mixture was allowed to stand at room temperature overnight. The mixture was treated with ammonium chloride aqueous solution and partitioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was separated and washed successively with 1N hydrochloric acid (twice), sodium bicarbonate aqueous solution, and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed (n-hexane - ethyl acetate (10:1)) over silica gel. The first eluate afforded 2-[(1RS,2RS)-1-hydroxy-2-[(3-methoxyphenyl)methyl]-cyclohexyl]-4,5-diphenyloxazole (4.48 g) as pale yellow paste.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:30]#[N:31])[CH:26]=3)[C:21]2=[O:32])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[OH:38][C:36]([C:35]([F:40])([F:39])[F:34])=[O:37].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:30]#[N:31])[CH:26]=3)[C:21]2=[O:32])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(N2C(=O)c3ccc(C#N)cc3C2=O)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(N2C(=O)c3ccc(C#N)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 4-(5-cyano-1,3-dioxo-2H-isoindol-2-yl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (1.33 mmol, 0.6 g) in dichloromethane (12 mL) was added trifluoroacetic acid (3 mL) at room temperature. The reaction mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. The solvent was removed under vacuum and the residue was azeotrophed with toluene (2×10 mL) and dried under high vacuum to afford 0.46 g (100%) of a yellow solid. HR MS (C19H15N3O4): Obs mass, 350.0156. Calcd mass, 350.0183 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:26]1([S:30](C2C=CC(C3C=C4N=C(CCC5NC(=S)CCCC5)NC4=NC=3)=CC=2)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27]1.N>CO>[N:26]1([S:30]([C:4]2[CH:3]=[CH:2][C:1]([C:7]3[CH:8]=[C:9]4[N:15]=[C:14]([CH2:16][CH2:17][CH:18]5[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]5)[NH:13][C:10]4=[N:11][CH:12]=3)=[CH:6][CH:5]=2)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Reactant: O=S(=O)(c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1)N1CCC1
Agent: N
Solvent: CO
Product: NC1=NC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)CCCC1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 92 mg of 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione (compound A6) and 4.50 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 70 hours. Purification by flash chromatography on LiChroprep-NH2® (eluent gradient: dichloromethane/0-100 vol. % methanol) affords 56 mg of the title compound as an amorphous solid of m.p. 154° C. (decomp.). ESI-MS: 453.2 (MH+). TLC: Rf=0.23 (LiChroprep-NH2® HPTLC, neat methanol).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC(CN)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC(CNC(=O)c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
0.22 g of benzoyl chloride was added to 10 ml of a solution of 0.25 g of N-(methoxycarbonyl)-1-phenylethylenediamine and 0.2 g of triethylamine in dichloromethane under ice cooling, and the mixture was stirred for 30 minutes at 5° C. and at room temperature for 3 hours. The reaction mixture was rinsed with water, the organic layer was dried over magnesium sulfate anhydrous, and the residual oily material obtained under a reduced pressure was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to obtain 0.28 g of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[S:23][CH:24]=[C:25]([CH2:26]OCOC)[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.Cl.N12CCCN=C1CCCCC2.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[N:60]([CH2:26][C:25]1[C:20]2[S:19](=[O:31])(=[O:32])[N:18]=[C:17]([C:8]3[C:7](=[O:33])[N:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:22][C:21]=2[S:23][CH:24]=1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 97.1 %

Procedure:
To the product of Example 353C (384.7 mg, 0.78 mmol) was added a solution of hydrogen chloride in dioxane (4N, 7.8 mL) at 0° C. The solution warmed to room temperature and stirred for 5.5 hours and concentrated under reduced pressure. This solid was suspended in dichloromethane (7.8 mL) and to the suspension was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL, 4.01 mmol) and diphenylphosphoryl azide (0.85 mL, 3.94 mmol) at room temperature and stirred overnight. The solution was concentrated in vacuo. The residue was purified by chromatography, eluting with 1% triethylamine/dichloromethane to give a triethylamine salt of the title compound (357 mg, 79%). MS (ESI−) m/z 470 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.22 (m, 2 H) 0.46 (br d, J=7.35 Hz, 2 H) 1.01 (m, 1 H) 4.52 (s, 2 H) 5.98 (t, J=6.62 Hz, 1 H) 7.24 (s, 1 H) 7.40 (m, 1 H) 7.56 (m, 1 H) 8.05 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:24]4[N:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccnc21
Product: CC1c2ncccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])=[O:20]>>[CH:1]1([CH2:4][N:5]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:19]([O:18][CH3:17])=[O:20])[CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCCC(=O)Cl
Reactant: c1ccc2c(CCNCC3CC3)c[nH]c2c1
Product: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)CC1CC1
Yield: 60.2 %

Procedure:
10.5 g of N-cyclopropylmethyl-tryptamine (i.e., 3-(2-cyclopropylmethylaminoethyl)-indole) and 9.7 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 10.1 g of N-cyclopropylmethyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-cyclopropylmethyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 60.3%
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 3-(4-hydroxyphenyl)propionic acid (20.0 g, 0.12 mol) and benzyl bromide (21.5 mL, 0.18 mol) in 155 mL of THF is added, at ambient temperature to a 1N aqueous solution of soda (301 mL). The phase transfer catalyst, Bu4NHSO4 (155 mg, 0.45 mmol), is finally added. The reaction medium is stirred overnight before being heated for 1 h at 80° C. After cooling down, 150 mL of a 1N aqueous solution of HCl is added slowly. After extraction with CH2Cl2, the organic phases are dried over MgSO4, filtered and concentrated under vacuum. Purification is carried out on silica gel (CH2Cl2 up to CH2Cl2/MeOH 95:5) in order to produce compound 2 (30.4 g, 0.12 mol, 99%) in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:23])=[C:4]([C:8]2[CH:9]=[C:10]([CH3:22])[C:11]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH2:28]([O:30][C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C>CO>[CH3:28][O:30][C:31]1([NH:1][C:2]2[C:3]([CH3:23])=[C:4]([C:8]3[CH:9]=[C:10]([CH3:22])[C:11]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:33][CH2:32]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Cc1cc(-c2cccc(N)c2C)cnc1N(C)C(=O)C(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: COC1(Nc2cccc(-c3cnc(N(C)C(=O)C(C)(C)C)c(C)c3)c2C)CC1
Yield: 100 %

Procedure:
To a suspension of 5.70 g of N-[5-(3-amino-2-methyl-phenyl)-3-methyl-2-pyridyl]-N,2,2-trimethylpropanamide in 34.2 ml of methanol were added 4.40 g of acetic acid and 4.32 g of 1-ethoxy-1-trimethylsilyloxycyclopropane and the mixture was refluxed for 7 hours under a nitrogen atmosphere. Concentration of the reaction mixture under reduced pressure afforded 6.98 g of N-(5-{3-[(1-methoxycyclopropyl)amino]-2-methylphenyl}-3-methyl-2-pyridyl)-N,2,2-trimethylpropanamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:21]([F:23])[F:22])=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Na+]>C(O)C>[C:15]1([N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:21]([F:22])[F:23])=[N:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(C(F)F)nn(-c2ccccc2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C(F)F)nn(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
N-Phenyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (3.0 g, 9.0 mmol) in ethanol (15 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (3.4 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (40 ml) and extracted with diethyl ether (20 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×30 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-Phenyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid (2.58 g, 8.43 mmol, 94%) was isolated as a colourless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([O:10][C:11]2[C:12]([CH3:26])=[C:13](C)[C:14]3[O:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=O)[C:15]=3[C:23]=2[CH3:24])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.CO[CH:47]([O:50]C)[O:48][CH3:49]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:11]2[C:23]([CH3:24])=[C:15]([CH3:16])[C:14]3[O:19][C:18]([CH3:20])([CH3:17])[CH:21]([C:47]([O:48][CH3:49])=[O:50])[C:13]=3[C:12]=2[CH3:26])=[O:9])=[CH:27][CH:28]=1)([O-:3])=[O:2]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)CC(C)(C)O2
Reactant: COC(OC)OC
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: CO
Solvent: O
Product: COC(=O)C1c2c(C)c(OC(=O)c3ccc([N+](=O)[O-])cc3)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 84 %

Procedure:
A heterogeneous mixture of 30.20 g (0.079 mol) of 3,4-dihydro-6-(4-nitrobenzoyl)oxy-2,2,5,7,8-pentamethyl-2H-1-benzopyran-4-one, 36.86 g (0.083 m) of thallium (III) nitrate trihydrate, 200 ml of trimethylorthoformate, and 200 ml of methanol is stirred at room temperature for 4 days. The resulting solid is collected and washed with methanol. The residue is slurried in 100 ml of chloroform and filtered; this process is repeated three times. The combined filtrates are heated to boiling and the chloroform is gradually replaced by an equal volume of methanol until crystallization occurs to give 27.44 g (84%) of 2,3-dihydro-5-(4-nitrobenzoyl)oxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid, methyl ester, m.p. 215°-216° C. Elemental analysis, IR, UV, and 1H-NMR spectra confirm the structure. This procedure was scaled up to 402 g, and 380.9 g (87.8%) of product was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]([NH:19][P:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)([CH3:3])[CH3:2].[CH2:27]([Li])CCC.CI>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]([N:19]([P:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:27])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=Nc2ccccc2C(C)C)NP(C(C)C)C(C)C)cc1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CI
Product: Cc1ccc(C(=Nc2ccccc2C(C)C)N(C)P(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
N′-(2-isopropylphenyl)-N-(diisopropylphosphino)-4-methylbenzamidine (1.40 g, 3.0 mmol) was dissolved in 25 mL of diethylether and cooled to 0° C. Butyllithium (1.50 mL of 2.0 M solution in pentane, 3.0 mmol) was added dropwise, producing a cloudy yellow suspension. The slurry was warmed to room temperature and stirred for 2 hours. Methyliodide (1.5 mL of 2.0 M solution in THF) was added dropwise at room temperature and stirred continued for 1 hour. The solution became clear yellow. The solvent was removed under vacuum and replaced with 20 mL of diethylether. A small amount of solid (presumably LiI) was removed by filtration and the filtrate was taken to dryness, yielding 0.94 g (65%) of sticky yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[S:21].[NH4+].[OH-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCOc1cc(Oc2cccnc2)cnc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1cc(Oc2cccnc2)cnc1NC(N)=S
Reaction time: 48 h
Yield: 69 %

Procedure:
3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-ylamine (0.48 mmol) is dissolved in THF (7 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 2 days. 32% NH4OH (20 eq.) is added and stirred 4 hours at room temperature. The solved is removed in vacuo and water (150 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-yl]-thiourea is obtained as yellow solid in a yield of 69%. HPLC (method C): 1.15 min; LC-MS (method A): 0.9 min, 321.15 (MH+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:51]=[CH:50][C:14]([CH2:15][C:16]2[C:17]([CH3:49])=[CH:18][C:19]([O:45][C:46](=[O:48])[CH3:47])=[C:20]([C@@H:22]3[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[CH:21]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[C:17]([CH3:49])=[CH:18][C:19]([O:45][C:46](=[O:48])[CH3:47])=[C:20]([C@@H:22]3[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[CH:21]=2)=[CH:50][CH:51]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(CCNC(=O)OC(C)(C)C)cc3)c(C)cc2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(CCN)cc3)c(C)cc2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a chloroform solution (80 mL) of (1S)-1-[5-[4-(2-tert-butoxycarbonylaminoethyl)benzyl]-2-acetoxy-4-methylphenyl]-1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol was added trifluoroacetic acid (23 mL), and the mixture was stirred for 1.5 hours at room temperature. The solvent was evaporated under reduced pressure to obtain a residue. Thus obtained residue was diluted with chloroform, and washed with a saturated sodium bicarbonate aqueous solution and brine. This solution was dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain the title compound (4.67 g, quant.) as a colorless powder.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)(C)(C)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:11][C:9]1[CH:10]=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cccc(C)c1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
81 parts of 5-tert.-butyl-m-xylene and 70 parts of benzoyl chloride are kept with 2.4 parts of ferric chloride for three hours at from 100° to 120°C. The whole is cooled to 25°C and 600 parts of benzene and 100 parts of aluminum chloride are added. 20 parts of hydrogen chloride is passed into the mixture during six hours at 70° to 80°C. The mixture is poured onto 1000 parts of ice-water. The organic phase which forms is separated and 77 parts (73.3% of theory) of 2,6-dimethylbenzophenone having a boiling point of 122° to 125°C is isolated by distillation at 0.3 mm Hg.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][CH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:40])[CH3:41]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC[C@@H]1CCCN1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)[Si](OC[C@@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Temperature: 60 °C
Yield: 28 %

Procedure:
To a solution of Intermediate A (50 mg, 0.309 mmol) in DMF (2 mL) was added NaH (60% in oil, 33 mg, 0.80 mmol) and the mixture stirred at RT for 20 min, before Intermediate 28b (110 mg, 0.280 mmol) was added. This mixture was heated at 60° C. in the microwave for 1.25 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH3 in MeOH] in DCM gave the title compound as a viscous yellow oil (42 mg, 28%). LCMS (Method 4): Rt 2.55 min, m/z 536 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: S=C=Nc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=S)Nc4ccccc4)cc23)CC1
Yield: 70.4 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 13.26 mg (0.098 mMol) phenyl isothiocyanate, 16.8 mg (71%) of the title compound were recovered.