Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C1COCC1.[Si]([O:14][C:15]1[C:19]2[C:20]([CH3:40])=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]=2[O:17][CH:16]=1)(C(C)(C)C)(C)C>O.C(=O)(O)[O-].[Na+]>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]4[O:17][CH2:16][C:15](=[O:14])[C:19]=4[C:20]=3[CH3:40])[CH2:31][CH2:30]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4occ(O[Si](C)(C)C(C)(C)C)c4c3C)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)CO4)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
1N hydrochloric acid (5 mL) was added to a solution of THF (25 mL) containing 1-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,6,7-trimethyl-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (560 mg, 1.16 mmol) synthesized in Reference Example 108, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with saturated sodium bicarbonate water. THF in the reaction mixture was removed under reduced pressure, and the residue was extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 85/15) to give 310 mg of the title compound (yield: 73%).
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CC(O)(C)C.[Br:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]([CH:73]([F:75])[F:74])=[CH2:72])=[CH:67][CH:66]=1.S([O-])([O-])=O.[Na+].[Na+].[OH2:82]>C(OCC)(=O)C>[Br:64][C:65]1[CH:66]=[CH:67][C:68]([C@:71]([OH:22])([CH:73]([F:74])[F:75])[CH2:72][OH:82])=[CH:69][CH:70]=1
Reactant: C=C(c1ccc(Br)cc1)C(F)F
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: OC[C@](O)(c1ccc(Br)cc1)C(F)F
Temperature: 25 °C

Procedure:
To a 250 mL flask charged with commercial AD-mix-beta (7 g) were added t-BuOH (25 mL) and H2O (25 mL). The mixture was stirred at room temperature to give 2 clear phases and the low phases appeared yellow orange. After cooling to 0° C., 1-bromo-4-[1-(difluoromethyl)vinyl]benzene (1.1 g, 4.7 mmol) was added at once and the mixture was stirred at approximately 4° C. overnight. A bright yellow mixture resulted. The mixture was kept at 0° C. and solid sodium sulfite (8 g, 64 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. Ethyl acetate (50 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×10 mL). Combined ethyl acetate extracts were dried (Na2SO4) and concentrated. Purification by combined Flash (40 g column; eluted with hexanes—Ethyl acetate (20% -60%) in 25 min.; flow rate: 35 mL/min and collected 18 mL/fraction) yielded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[B][B][B][B][B][B][B][B][B][B].CCOC(C)=O.CCCCCC>CO>[O:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:16]1
Reactant: O=C1CCOCC1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(F)(F)F)cc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a solution of 500 mg (2.46 mmol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone in methanol (18 ml) was added 250 μl (2.70 mmol) dihydro-2H-pyran-4(3H)-one at RT followed by the addition of 90 mg (0.73 mmol) decaborane. The reaction mixture was stirred at RT for 16 h. The mixture was evaporated under vacuum and residue diluted with ethyl acetate (20 ml). The organic layer was washed with water (20 ml), brine (20 ml), dried over anhydrous Na2SO4 and concentrated in vacuum. After CC (EtOAc/hexane 1:24) of the residue, 240 mg (0.83 mmol, 34%) 1-(2-(tetrahydro-2H-pyran-4-ylamino)-4-(trifluoromethyl)phenyl)ethanone were obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.I[Si](C)(C)C.CO>C(#N)C.C(OCC)(=O)C>[CH:18]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[NH:14][N:13]=1)=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C(=C/c1n[nH]c2ccc(OCc3ccccc3)cc12)\c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc2[nH]nc(C=Cc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A solution of 652 mg of 5-benzyloxy-3-((E)-styryl)-1H-indazole in 60 ml of acetonitrile is stirred under argon. 1.13 ml of iodotrimethylsilane are added dropwise under an inert atmosphere. The suspension is stirred at approximately 50° C. for 3 hours and then at ambient temperature overnight. The medium is heated to around 50° C. and then 1.2 ml of iodotrimethylsilane are added. After stirring for 3 hours, 0.8 ml of iodotrimethylsilane is added. After stirring for approximately 4 hours, the medium is treated with 10 ml of methanol and stirred at ambient temperature for about fifteen minutes. The suspension is filtered through a paper filter and the filtrate is concentrated under vacuum in a rotary evaporator. The reaction crude is taken up in 50 ml of ethyl acetate and the organic phase is washed with 2×50 ml of a sodium thiosulfate solution, 2×50 ml of a saturated sodium bicarbonate solution, and 50 ml of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and then concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on silica (Varian 20 g cartridge), eluent: ethyl acetate/cyclohexane gradient 5:95 to 35:65 to obtain 265.4 mg of 3-styryl-1H-indazol-5-ol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.O1CCCC1.[H-].[Na+:16].[C:17](=[S:19])=[S:18]>>[O:1]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:17]([S-:19])=[S:18].[Na+:16]
Reactant: S=C=S
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C([S-])OCCN1CCOCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4.91 g. of N-(2-hydroxyethyl)morpholine in 250 ml. of anhydrous tetrahydrofuran at room temperature was added 1.79 g. of a 50% dispersion of sodium hydride in mineral oil. A precipitate formed. The mixture was stirred for 30 minutes, and then 2.75 ml. of carbon disulfide was added, causing the initial precipitate to dissolve. The reaction mixture was stirred for 30 minutes during which time a further precipitate formed. To the mixture was added 200 ml. of anhydrous ether, and the precipitate was recovered by filtration. The solid was washed with ether, and dried, to give 8.8 g. of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([CH3:15])[CH:9]=1.[Cl-].[NH4+].O1CC[CH2:21][CH2:20]1>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([OH:16])([CH2:1][CH3:2])[CH2:20][CH3:21])=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)(CC)c1ccc(Br)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 73 mL, 218.3 mmol) was added to a solution of 4-bromo-3-methylbenzoic acid methyl ester (20 g, 87.31 mmol) in tetrahydrofuran (120 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (21.86 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH:20](C3C=CC(F)=CC=3)[CH2:21][CH:16]2[CH2:15]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH2:20][CH2:21][CH:16]2[CH2:15]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCCC1CC2CC(c3ccc(F)cc3)OC2O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1NCCC1CC2CCOC2O1
Reaction time: 8 h
Yield: 78.3 %

Procedure:
4Chloro-3-nitropyridine (160 mg, 1.0 mmol) is added to a stirred solution of 5-(2-aminoethyl)-2-(4-fluorophenyl)hexahydrofuro[2,3-b]furan (200 mg, 0.8 mmol) and triethylamine (1.0 ml) in chloroform (15 ml) at ambient temperature. The reaction mixture is stirred overnight, then washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to leave an orange oil. This is purified by chromatography over silica (1:1 ethyl acetate/hexane) to give 2-(4-fluorophenyl)-5-(2-(N-3-nitropyrid-4-ylaminoethyl)hexahydrofuro[2,3-b]furan (175 mg, 59%) as a yellow amorphous solid.
Reaction SMILES: C[O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ccnc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cn2ccnc2)cc1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a stirred solution of the compound of Step A (16.3 g, 86.1 mmole) in methylene chloride (860 ml) cooled to 5° C., was added boron tribromide (32.6 ml, 344.4 mmole) dropwise over 15 minutes. After 2 hours at 5° C., the reaction was quenched with methanol dropwise, evaporated to dryness, and redissolved in methanol, water, and methylene chloride. The pH was adjusted to 8.4 with sodium hydroxide. The organic layer was dried over sodium sulfate and evaporated to dryness to give N-p-hydroxybenzylimidazole (13.6 g, 91%) which was used without further purification:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:3]1[C:2]([NH:1][S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[C:10]2[C:6]([CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2ccc(C)c(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccc(C)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.1 %

Procedure:
To a mixed solution of ethyl 7-amino-6-methyl-1H-indole-2-carboxylate (0.50 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.54 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:3), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (677 mg, yield 81%) as colorless needle crystals. melting point 184-185° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:40]([N:47]=[C:48]=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:40]([NH:47][C:48](=[O:49])[O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 35 °C
Reaction time: 24 h

Procedure:
To a solution of hemi-aminal A1 from Example 1 (4 g, 8.4 mmol), 4-dimethylaminopyridine (0.15 g, 1.3 mmol) and triethylamine (1.1 mL, 7.5 mmol) in dichloromethane (30 mL) was added benzylisocyanate (1.03 mL, 8.3 mmol) and the reaction mixture stirred for 24 hours. The reaction mixture was then heated at 35° C. for 20 hours, cooled and washed with water/brine (1:1, 50 mL). The organic phase was dried over MgSO4, filtered and evaporated under vacuum. The residue was further purified by chromatography on silica eluting with ethyl acetate/dichloromethane/methanol (1:1:0.1) to give the desired product as an off white foam (530 mg, 14% yield). 1H NMR (CDCl3, 300 MHz) δ 1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H), 300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H), 6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16 (m, 1H), 7.23-7.35 (m, 6H); m/z (M+H) 611.12 and 613.10.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in N,N-dimethylformamide was treated with potassium carbonate (2.71 g, 19.6 mmol) and 1-bromomethyl-cyclopropane (1.6 ml, 15.7 mmol). The reaction mixture was stirred at 100° C. for 16 hours. For the workup, the reaction mixture was diluted with ethyl acetate, solid material was filtered, and the filtrate evaporated at reduced pressure. The residue was purified by chromatography on silica using a gradient of n-heptane and ethyl acetate=100/0 to 20/80 as the eluent to give the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester as a yellow liquid (1.69 g, 62% of theory). Mass (calculated) C11H13NO3 [207.228]; (found) [M+H]+=208.
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[O:7]1[CH2:6][CH2:5][S:1][CH2:2][CH2:3][O:4][C:16]1=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCSCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCCSCCO1

Procedure:
The procedure of Example 1 was followed using 2,2′-thiodiethanol (10.2 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding only oligomeric compounds.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH:8](O)[CH:9]=[C:10]([Cl:12])[Cl:11])[CH2:3][CH2:4]C(O)=O.S(Cl)(Cl)=[O:16].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:4]([CH:3]1[C:2]([CH3:1])([CH3:14])[CH:8]1[CH:9]=[C:10]([Cl:11])[Cl:12])=[O:16])[CH3:20]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CCC(=O)O)C(O)C=C(Cl)Cl
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reaction time: 14 h
Yield: 81 %

Procedure:
5.25 g (0.025 mol) of the lactone of 3,3-dimethyl-4-hydroxy-6,6-dichlorohex-5-enecarboxylic acid with 15 ml of thionyl chloride is held for 3 hours at 70° C. An addition of 20 ml of ethanol is then made, and the reaction mixture is allowed to stand for 14 hours at room temperature. The reaction mixture is concentrated by evaporation, and the residue is treated briefly with sodium ethylate in ethanol, as described in Example 3. After customary processing, there is obtained in 81% yield the 2-(2',2'-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid ethyl ester having a cis-trans ratio of approximately 1:4, determined according to NMR spectrum.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=O)[CH2:12][CH2:13][C:14]2([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=[N:30][NH2:31])[CH2:12][CH2:13][C:14]2([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2(C)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2(C)c1ccccc1
Yield: 90 %

Procedure:
A solution of 3 g (7.95 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-methyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate and of 1.55 cm3 (31.8 mmol) of hydrazine hydrate in 30 cm3 of methanol was brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue was taken up in dichloromethane, washed with three times 30 cm3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 2.8 g (89%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-methyl-4-phenyloctahydroisoindole-3a-carboxylate were thus obtained in the form of a brown oil, the characteristics of which were as follows:
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Si:15]([CH2:20]C)([CH2:18]C)[CH2:16]C)[CH:10]=2)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:4]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:3]1.C(O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Si:15]([CH3:16])([CH3:18])[CH3:20])[CH:10]=2)[NH:6][C@@H:5]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C@@H:4]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:3]1
Reactant: CC[Si](CC)(CC)c1cccc(C[C@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)c1cccc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)c1
Yield: 92.4 %

Procedure:
According to example 82, 2.47 g of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(triethylsilyl)benzyl)-4-morpholinecarboxylate was treated with 4.1 mL of TFA in 40 mL of CH2Cl2 for 3 h. Neutralization with 8 mL of Et3N and work-up in the usual manner gave a thick oil. Purification of the crude material by flash chromatography on 80 g of silica gel (85:15 hexane:EtOAc) afforded 1.70 g (83%) of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(trimethylsilyl)benzyl)morpholine as a white crystalline solid, m.p. 94-95° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.Cl[C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[CH:13][N:12]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][CH3:1])[N:4]=2)[CH:16]=1
Reactant: CNc1cccc(N)n1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNc1cccc(Nc2cc(Cl)ncn2)n1
Temperature: 120 °C
Yield: 31.5 %

Procedure:
A mixture of 2-methylamino-6-aminopyridine (0.5 g, 4.04 mmol), 4,6-dichloropyrimidine (1.51 g, 10.13 mmol), DIPEA (1.5 g, 12.17 mmol) in n-butanol (5 mL) was heated at 120° C. for 16 h. The reaction mixture was cooled, was concentrated under reduced pressure and the residue was taken in dichloromethane (25 mL). The dichloromethane solution was washed with NaHCO3 solution (2 mL), water (2 mL) and brine (2 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, petroleum ether/ethyl acetate, 6/4) to give N2-(6-chloropyrimidin-4-yl)-N6-methylpyridine-2,6,diamine (0.3 g, 33%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.Cl[CH2:22][CH:23]=O>C(O)C>[S:19]1[CH:23]=[CH:22][N:20]=[C:18]1[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Reactant: O=CCCl
Solvent: CCO
Product: O=C1Nc2ccccc2Nc2ccc(Nc3nccs3)cc21
Yield: 40 %

Procedure:
To a solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 75 mg, 0.26 mmol) in ethanol (10 mL) was added chloroacetaldehyde (50% in water, 0.1 mL). The solution was refluxed for 5 hr and then concentrated under vacuum and poured into water (5 mL). The solution pH was adjusted to 9 with aqueous saturated sodium bicarbonate and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent evaporated. The residue was recrystallized from ethanol/hexanes to give yellow solid (30 mg, 40%).
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].C([NH:20][C:21]#[N:22])(=O)C1C=CC=CC=1>C(O)C.Cl>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:21]([NH2:22])=[NH:20])=[CH:7][CH:8]=1)(=[O:10])(=[O:2])[NH2:11]
Reactant: N#CNC(=O)c1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
A mixture of sulphanilamide (20 g, 0.166 mol), benzoyl cyanamide (34 g, 0.33 mol) in ethanol (60 ml) and concentrated hydrochloric acid (11 ml) was heated on a steam bath until the solvent had evaporated. Water was added and the mixture heated at reflux for 5 minutes. Sodium hydroxide (14.4 g) was added and the mixture heated at reflux. The mixture was allowed to cool and was adjusted to pH2 with hydrochloric acid and the precipitated solid removed by filtration. The filtrate was neutralised and the solvent removed by evaporation. The residue was recrystallized from water to give the crude title product. m/z: 215 [MH]+.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cccc(C(=O)Nc2ccc3nc(Nc4ncnc5cc(OC)c(OC)cc45)sc3c2)c1

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-methoxybenzamide was prepared from m-anisoyl chloride (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 41 mg, 84 μmol, 74%). LC/ESI-MS: m/z=488 [M+H]+; m/z=486 [M−H]−; Rt=3.17 min.