Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([CH2:14][CH2:15][OH:16])[CH2:8][CH:9](O)[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:14][CH2:15][O:16][CH:9]([CH:10]([CH3:12])[CH3:11])[CH2:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(O)CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C1CN(C(=O)OC(C)(C)C)CCO1
Reaction time: 8 h

Procedure:
The above compound could be made in the following manner: 1 eq. of (2-Hydroxy-ethyl)-(2-hydroxy-3-methyl-butyl)-carbamic acid tert-butyl ester and 1.2 eq. of triphenylphosphine could be dissolved in toluene. 1.2 eq. of diethylazodicarboxylate in toluene could be added dropwise to the resulting solution at room temperature under argon atmosphere and the mixture could be stirred overnight. The solvent could be removed in vacuo and the material purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.C([Mg])(C)C.CN([CH:16]=[O:17])C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:16]=[O:17])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(I)nc1
Agent: CC(C)[Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cn1
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 5-bromo-2-iodopyridine (14.2 g, 50 mmol) in dry THF (160 mL) was added dropwise isopropylmagnesium (30 mL, 60 mmol) at −20 degrees Celsius under N2. After addition, the reaction mixture was stirred for about 2 h at the same temperature, and then DMF (5.11 g, 70 mmol) was added while keeping the temperature under 0 degrees Celsius. The reaction temperature was allowed to rise to rt and stirred for 1 hour, quenched with saturated ammonium chloride (10 ml), and then the solution pH was adjusted to 7-8 with 2.0 M HCl. The solvent was removed and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain 8.5 g (90%) of a yellow solid product which was used directly in the next step without further purification. MS: calc'd 186 (MH+), exp 186 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]1.Br[CH2:19][N:20]1[C:24](=[O:25])[C:23]2[C:26]([CH:32]([CH3:34])[CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[S:21]1(=[O:36])=[O:35].[F-].[K+]>CN(C=O)C.O>[CH:32]([C:26]1[C:23]2[C:24](=[O:25])[N:20]([CH2:19][O:13][C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=3)[S:21](=[O:36])(=[O:35])[C:22]=2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=1)([CH3:34])[CH3:33]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: O=C1CC(C(F)(F)F)=NN1c1ccccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1Cl)C2=O
Yield: 43 %

Procedure:
A mixture 2,4-dihydro-2-(2-chlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (543 mg; 2.06 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (600 mg, 1.72 mmol) and KF (250 mg, 3.44 mmol) in 7 ml of DMF was stirred at room temperature for 4 hours. The mixture was diluted with water, extracted with ether (3×), and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (2×, silica gel; 12-50% ethyl acetate in hexane; 10-50% methylene chloride/ethyl acetate) and recrystallized from ethyl acetate/hexane to afford 392 mg (43%) of 4-isopropyl-6-methoxy-2-[1-(2-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =2-Cl--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as m.p. 134-1360° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=C)=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=[O:26])=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: C=Cc1cc2c(s1)n(Cc1ccc(OC)cc1)c(=O)n1ncnc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)sc32)cc1
Reaction time: 4 h
Yield: 63.5 %

Procedure:
6-(4-Methoxybenzyl)-8-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (2.85 g; 8.42 mmol) was suspended in tetrahydrofuran (40 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (4.14 g; 19.4 mmol) was heated in water (20 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was still about 40° C., osmium(VIII) oxide (2.06 ml, 2.50% w/w, 0.21 mmol) was added and the mixture was stirred vigorously for 4 hours. The crude mixture was diluted with water (300 mL) and extracted with DCM (4×100). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified over silica gel (120 g) eluting with 0-30% IPA in ethyl acetate over 25 minutes. Product fractions were combined and concentrated to yield the aldehyde as a brown solid (1.82 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3H), 5.40 (s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.45 (d, J=8.53 Hz, 2H), 8.58 (d, J=4.77 Hz, 2H), 9.95 (s, 1H). LCMS (MH+, 341.2).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)C.SCC(C(CS)O)O.ClC1N2[N:31]=[C:32]([O:35][CH2:36][CH3:37])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1>O.P([O-])(O)(O)=O.[K+]>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]2[N:13]([C:12]([S:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH2:1])[S:3][C:4]=4[CH:10]=3)=[N:27][N:28]=2)[N:31]=1)[CH3:37]
Reactant: CCOc1ccc2nnc(Cl)n2n1
Reactant: N#CSc1ccc2nc(N)sc2c1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc2nnc(Sc3ccc4nc(N)sc4c3)n2n1
Yield: 80.3 %

Procedure:
The 6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 17a, but using 587 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial), 20 cm3 of degassed ethanol, 13 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 1.31 g of DL-dithiothreitol and 562 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine. 783 mg of 6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-amine are thus obtained in the form of a whitish powder, the characteristics of which are as follows:
Reaction SMILES: CN[C@@H](C1C=CC=CC=1)CN1CCCCC1.[CH2:17]([Li])[CH2:18][CH2:19][CH3:20].[NH2-].[Li+].[C:24]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1>CSC.[Cu]I>[CH2:17]([C@H:26]1[CH2:27][CH2:28][CH2:29][C:24](=[O:30])[CH2:25]1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CCCC1
Reactant: [Li]CCCC
Agent: [Cu]I
Agent: CN[C@H](CN1CCCCC1)c1ccccc1
Agent: [Li+]
Solvent: CSC
Product: CCCC[C@H]1CCCC(=O)C1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 56.6 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (139.0 mg, 0.638 mmol) was dissolved in dimethyl sulfide (4 mL) and n-butyl lithium (2.5M in hexanes, 0.255 mL, 0.638 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., gradually warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (81 mg, 0.425 mmol) and 4 mL of dimethyl sulfide. This solution was cooled to -40° C. and treated with n-butyl lithium (0.17 mL, 0.425 mmol). The lithium amide solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to - 78° C. After 30 min, 2-cyclohexenone (40.8 mg, 0.425 mmol) was added slowly at -78° C. The reaction mixture was quenched after 1 hr by adding 4N NH4Cl (15 mL) at -78° C. and extracted with ether (15 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (10:1=hexanes/ethyl acetate) to afford (S)-3-n-butylcyclohexanone (37.1 mg, 57% chemical yield, 83% ee, [α]D =-7.10 (c=1.00, toluene)).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Fe+2:6].[N+:7]([O-])([O-])=O.[NH4+]>>[NH4+:7].[O-:4][S:1]([O-:5])(=[O:3])=[O:2].[O-:4][S:1]([O-:5])(=[O:3])=[O:2].[Fe+3:6]
Reactant: O=[N+]([O-])[O-]
Reactant: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: [Fe+3]

Procedure:
The method of claim 27 wherein the solution of iron sulfate is contacted with aqueous ammonium nitrate at a temperature of about 90° C. to about 150° C. to form a solution of ammonium jarosite and/or ferric ammonium sulfate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:41]5[CH:40]=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[CH:42]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: COc1cccc(B(O)O)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(OC)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-methoxyphenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Cl.Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: ClCCCCc1ccncc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 12.2 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (221 mg, 0.677 mmol) in N,N-dimethylformamide (4 mL) was mixed with 4-(4-chlorobutyl)pyridine hydrochloride (278 mg, 1.35 mmol) and potassium carbonate (375 mg, 2.71 mmol) at room temperature and stirred at 80° C. for 6.5 hours. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=50/1) to give the desired product (38 mg, 12% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18]1>O1CCCC1>[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([O:22][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18]1
Reactant: CN1CC[C@H](O)C1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 42.3 mmol, Aldrich) in tetrahydrofuran (50 mL) were added sodium hydride (1.9 g, 46.5 mmol, 60% in mineral oil) and (S)-1-methylpyrrolidin-3-ol (4.7 mL, 46.5 mmol, Aldrich). After stirring at room temperature for 3 h, the reaction mixture was quenched with saturated NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 10.9 g of the title compound. MS (ESI+) m/z 271 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH:2]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2ccccc2)N1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 5-(3-hydroxy-4-phenyl-butyl)-pyrrolidin-2-one (4.3 g, 18.43 mmol) in DMF (86 mL) was added tert-butyldimethylsilyl chloride (3.06 g, 20.3 mmol) followed by imidazole (2.5 g, 37 mmol) and DMAP (225 mg). The reaction mixture was stirred for 24 h and was quenched with saturated aqueous ammonium chloride. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2to 2% MeOH in CH2Cl2) to yield 5.94 g of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.26-7.10 (m, 5H), 5.68 (m, 1H), 3.83 (m, 1H), 3.54 (m, 1H), 2.69 (m, 2H), 2.30-2.16 (m, 3H), 1.66-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.2 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26].CC(C)=O>CCCCCC>[CH:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:27])[CH3:26]
Reactant: CC(C)I
Reactant: O=S1(=O)c2ccccc2Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O
Reaction time: 8 h

Procedure:
A mixture of 1.00 gm (0.0043 mole) of 3-hydroxyphenoxathiin 10,10-dioxide (Example 7) 1.48 gm (0.0107 mole) of anhydrous granular potassium carbonate, 5.5 mL of 2-iodopropane (Aldrich Chemical Co.), and 60 mL of acetone were stirred overnight. The acetone was removed under water pump vacuum and the residue mixed with methylene chloride and filtered. The filtrate was washed with 2×200 mL of water and dried over magnesium sulfate. The solvent was removed under water pump vacuum to give an oil. Some hexane was added to the oil and the mixture heated on a steam bath. This gave a white solid which was recrystallized from ethyl acetate/hexane to yield 0.75 gm of 3-isopropoxyphenoxathiin 10,10-dioxide, m.p. 94-95°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(OC([N:34]1[CH2:39][CH2:38][N:37]([C:40](=[O:43])[CH2:41]Cl)[CH2:36][CH2:35]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:41][C:40](=[O:43])[N:37]2[CH2:38][CH2:39][NH:34][CH2:35][CH2:36]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc21)N1CCNCC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available 4-(2-chloro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester as electrophile, the title compound was obtained as a white solid after removal of the Boc protecting group under standard conditions (TFA/dichloromethane, room temperature).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:22]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:22][C:4]1[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=1[O:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])=[CH:9][CH:8]=1
Reactant: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 98.4 %

Procedure:
The product from Example 126d (1.0 g, 2.85 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a clear oil (900 mg, 100%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH:21][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(c1ccccc1)C(O)c1ccccc1
Yield: 69.1 %

Procedure:
A stirred mixture of trans-stilbene oxide (6.48 g, 0.033 mol), and glycine ethyl ester (6.15 g, 0.0598 mol) was heated at 120° for 22 hours. The mixture was triturated with ether and filtered to remove some insoluble materials. The filtrate was concentrated to yield 6.83 g (69.1%) of oil which solidified into a waxy solid upon cooling. The compound was purified and characterized as the hydrochloride salt, mp 185°-187° C. (absolute ethanolisopropyl ether) [reported mp 167°, Can. J. Chem. 45, 2865 (1967)].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[K+].[O-]Cl.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=C(COCc1ccccc1)COCc1ccccc1
Temperature: -10 °C
Yield: 179.5 %

Procedure:
A solution of 1,3-dibenzyloxy-2-propanol (500 g, 1.84 mol, 1.0 eq.), TEMPO (5.5 g, 0.034 mol) in dichloromethane (1.25 L) was placed in a 10 L flange flask fitted with overhead stirrer. A solution of potassium bromide (48 g, 0.40 mol) in water (185 ml) was added and the reaction stirred and cooled to −10° C. A 14% aqueous NaOCl solution was diluted to 1M (2145 g diluted to 4050 ml). The pH of this solution was then adjusted to 9.5 by dissolving NaHCO3 (80 g) immediately before use. This NaOCl solution was added over 1 hour, keeping the temperature of the reaction mixture between 10-15° C. The mixture was the stirred for 60 minutes. The orange coloured organic phase was separated and the aqueous layer was extracted with dichloromethane (5.0 L, 2.0 L). The combined organics were washed with 10% aq. HCl (10.75 L) containing potassium iodide (143 g), 10% aq. Na2S2O5 (5.0 L) and water (5.0 L). The organics were dried over MgSO4 and concentrated under reduced pressure to give the crude title compound (893 g, 90%). This compound was taken through to the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:22][CH2:21][C:5]2([CH2:9][N:8]([C:10]3[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH2:19])=[C:12]([CH3:20])[CH:11]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].C(O)(=O)C.[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([I:36])[CH:31]=[CH:30][N:29]=1>CO.[Pd]>[Cl:27][C:28]1[C:33]([C:34]2[NH:16][C:14]3[CH:15]=[C:10]([N:8]4[CH2:7][CH2:6][C:5]5([CH2:21][CH2:22][N:3]([CH2:1][CH3:2])[CH2:4]5)[CH2:9]4)[CH:11]=[C:12]([CH3:20])[C:13]=3[N:19]=2)=[C:32]([I:36])[CH:31]=[CH:30][N:29]=1
Reactant: CCN1CCC2(CCN(c3cc(C)c(N)c([N+](=O)[O-])c3)C2)C1
Reactant: O=Cc1c(I)ccnc1Cl
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(I)ccnc5Cl)[nH]c4c3)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a solution of 4-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-2-methyl-6-nitro-phenylamine (304 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and then filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (5:1, CH2Cl2/MeOH) to afford the title compound (450 mg, 86%). 1H NMR (MeOH-d4) δ 1.38 (t, J=8 Hz, 3H), 2.10-2.21 (4H), 2.56 (s, 3H), 3.28-3.57 (10H), 6.55 (s, 1H), 6.57 (s, 1H), 8.03 (d, J=6 Hz, 1H), 8.13 (d, J=6 Hz, 1H). ESI-MS m/z 522 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22](=O)[CH2:23][CH2:24][C:25]([O:27]C)=O)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:30][NH2:31]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22]4[CH2:23][CH2:24][C:25](=[O:27])[NH:30][N:31]=4)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(OC)cc1)C2
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)NC2Cc3ccc(C4=NNC(=O)CC4)cc3C2)cc1

Procedure:
5.0 g (12 mmol) of methyl 4-(2-p-methoxybenzenesulphonamido-indan-5-yl)-4-oxobutyrate and 3.0 g (60 mmol) of 99% hydrazine in 25 ml of glacial acetic acid are boiled for 30 minutes. The mixture is evaporated, water is added to the residue, and the reaction product is filtered off with suction and recrystallised from n-propanol.
Reaction SMILES: SCC(C(CS)O)O.[S:9]([C:12]1[CH:25]=[CH:24][C:15]2[N:16]=[C:17]([NH:19][C:20](=[O:23])[O:21][CH3:22])[S:18][C:14]=2[CH:13]=1)C#N>O.C(O)C.P([O-])(O)(O)=O.[K+]>[SH:9][C:12]1[CH:25]=[CH:24][C:15]2[N:16]=[C:17]([NH:19][C:20](=[O:23])[O:21][CH3:22])[S:18][C:14]=2[CH:13]=1
Reactant: COC(=O)Nc1nc2ccc(SC#N)cc2s1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)Nc1nc2ccc(S)cc2s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
a solution of 5 mg of potassium dihydrogen phosphate in 1.1 cm3 of water at 20° C., followed by 480 mg of DL-dithiothreitol, are added to a white suspension of 280 mg of methyl (6-thiocyanato-1,3-benzothiazol-2-yl)-carbamate in 11 cm3 of ethanol at 20° C. The white suspension is stirred for 18 h at reflux. The reaction mixture is cooled to 20° C., then 10 cm3 of water are added and the mixture is stirred for 15 minutes. The precipitate is spin-filter-dried and then washed with large volumes of water. 231 mg of methyl (6-sulphanyl-1,3-benzothiazol-2-yl)carbamate are obtained in the form of a cream powder, the characteristics of which are as follows: