Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.[C:33]([O-])(=O)C.[Na+].C=O.[BH4-].[Na+].C(O)(=O)C.C(O)(=O)C.C(O)(=O)C>C(Cl)Cl.CO.C(O)(=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCNCC1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCN(C)CC1
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline (170 mg, 0.31 mmol), (prepared as described in Example 6), in methylene chloride (6 ml) and methanol (3 ml) was added a solution of sodium acetate (25 mg, 0.31 mmol). Acetic acid (22 ml) and formaldehyde (37%) (50 ml) were added. The mixture was stirred for 5 minutes and triacetate sodium borohydride (100 mg, 0.46 mmol) was added in portions. The mixture was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum and the residue was dissolved in water and the pH was adjusted to 10 with 2N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether, filtered, washed with ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)cinnoline (75 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]([CH3:18])[CH:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH3:18])[CH:8]([O:17][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: C[C@H](Oc1ccc(Br)cc1)C(O)CCc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](Oc1ccc(Br)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of (3RS,4S)-4-(4-Bromophenoxy)-1-pyridin-3-yl-pentan-3-ol (2.0 g, Example 4d)) in dry dichloromethane (50 ml) was added tert-butyldimethylsilyl chloride (1.17 g) and imidazole (1.08 g) and the resulting solution stirred for 24 hours, concentrated and the residue purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:4 to 1:1) to afford the sub-title compound as an oil (2.52 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[CH2:17]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH2:19].[F-].[Cs+].O1CCOCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[CH2:19]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH:18]=[CH2:17]
Reactant: Clc1cccc2c1CCOC2C1=NCCN1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=CCc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C

Procedure:
To a mixture of 2-(5-chloroisochroman-1-yl)-4,5-dihydro-1H-imidazole (50 mg), allyltributyltin (69.9 mg), CsF (70.6 mg) and bis(tri-t-butylphosphine)palladium (3.24 mg) were added dioxane (2 ml) and DMF (0.5 ml). The reaction mixture was degassed with N2 and heated in a microwave oven for 30 min at 160° C. The title compound was purified by applying methods F and G. (Yield 5.8 mg).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:24]3[C:36]4[NH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]=4[CH2:27][CH2:26][N:25]3[C:37]3[N:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47]C(OC)=C(OC)C=4)=[CH:39][N:38]=3)=[CH:18][C:17]=2[O:16]1.[CH2:53]1[CH2:57][O:56][CH2:55][CH2:54]1.O>C(OCC)(=O)C>[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:24]3[C:36]4[NH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]=4[CH:27]([OH:6])[CH2:26][N:25]3[C:37]3[N:38]=[CH:39][C:40]([C:43]4[CH:54]=[CH:53][C:57]([O:56][CH3:55])=[CH:47][CH:48]=4)=[CH:41][N:42]=3)=[CH:18][C:17]=2[O:16]1
Reactant: C1CCOC1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1OC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cnc(N3CC(O)c4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1
Temperature: 0 °C

Procedure:
To a mixture of DDQ (113.5 mg, 0.5 mmol) and 1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline (prepared as in Example 3) (51 mg, 0.1 mmol) was added a mixed solvent of THF:water (9:1) at −78° C. The mixture was stirred at 0° C. and allowed to warm to room temperature over a period of 15 h. Column chromatography (silica gel, hexanes:ethyl acetate=1:1) yielded the -oxo- and -hydroxy derivatives respectively, as white solids.
Reaction SMILES: [Cl:1]S([N:5]=[C:6]=[O:7])(=O)=O.[OH:8][CH2:9][C@@H:10]([NH:22]C(=O)OC(C)(C)C)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.O>C(#N)C>[ClH:1].[C:6](=[O:7])([O:8][CH2:9][C@@H:10]([NH2:22])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1)[NH2:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(C(F)(F)F)c1
Solvent: CC#N
Solvent: O
Product: Cl
Product: NC(=O)OC[C@@H](N)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −15° C., 51 μl (0.70 mmol) of chlorosulphonyl isocyanate were added slowly to a solution of 160 mg (0.50 mmol) of (2S)-tert-butyl {1-hydroxy-3-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate (for the preparation see US patent application 2008/0242694, Example [0464]) in 7.6 ml of acetonitrile. The reaction mixture was stirred at RT for 1 h, 1 ml of water was then added and the mixture was heated at 60° C. overnight. An analytical sample showed complete conversion into the target product according to LC/MS. After cooling to RT, the volatile components were removed on a rotary evaporator and finally under high vacuum. The residue (80 mg, 53% of theory) corresponded to the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13]C)=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2.[Cl-:15].[Ce+3].[Cl-].[Cl-]>>[Cl:15][C:12]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[NH:5][C:12]1[C:3](=[O:2])[C:4]2[N:5]=[CH:6][CH:7]=[N:8][C:9]=2[C:10](=[O:13])[CH:11]=1
Reactant: COc1ccc(OC)c2nccnc12
Reactant: [Cl-]
Agent: [Ce+3]
Product: O=C1C=C(Nc2cccc(Cl)c2)C(=O)c2nccnc21

Procedure:
Following the procedure of Example 5,3-chloroaniline was reacted with the aqueous solution of 5,8-dimethoxyquinoxaline in the presence of cerium chloride to give the title compound. Mass spectrum gave M+ of 285 and 287.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[CH2:10][CH2:11][C:12]#[CH:13])[CH:6]=[CH:7][CH:8]=1.[CH2:15]=O.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].[OH-].[Na+]>O1CCOCC1.C(O)(=O)C.O>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:15][C:13]#[C:12][CH2:11][CH2:10][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:14])[CH3:18]
Reactant: C=O
Reactant: CCNCC
Reactant: C#CCCC(C)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)CC#CCCC(C)c1cccc(OC)c1

Procedure:
Heat a mixture of 5-(3-methoxyphenyl)-hex-1-yne (56.6 g), water (17.5 cc.), 40% formalin (38.5 cc), diethylamine (40 cc), acetic acid (19 cc), dioxan (175 cc) and cuprous chloride (1 g) at 70° for 16 hours in an atmosphere of nitrogen. Make the cooled solution alkaline with 10% aqueous sodium hydroxide and extract twice with ether. Wash the ether extracts with water, filter and extract with 4N hydrochloric acid (3 × 350 cc). Make the acid extracts alkaline with 10% aqueous sodium hydroxide, extract with ether and wash the organic solution with water, brine and dry. Evaporate the solvent and distil the residue to obtain 1-diethylamino-6-(3-methoxyphenyl)-hept-2-yne, 79.5 g. b.p. 135°-140°/0.2 mm Hg nD25 1.5116.
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:22])[NH:16]2)[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6].C[O-:24].[Na+].N1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=CC1=O>CO>[CH:31]1([C:30]([O:21][C:18]2[CH:19]=[CH:20][C:11]([CH:3]([OH:2])[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6])=[C:12]3[C:17]=2[NH:16][C:15](=[O:22])[CH2:14][CH2:13]3)=[O:24])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2c1CCC(=O)N2
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)C2CCCCC2)c2c1CCC(=O)N2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
3.28 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxy-3,4-dihydrocarbostyril hydrochloride was dissolved in 50 ml of methanol, and a 10% methanolic solution of sodium methylate was added to the solution in an amount of 2 moles per mole of the starting carbostyril compound. The resulting mixture was concentrated to dryness, and the residue was dissolved in dimethylformamide. 1.6 g of cyclohexanecarboxylic acid chloride was added to the solution and the mixture was stirred for 2 hours at a temperature of 10° C. The reaction mixture was poured into ice-water and the mixture was extracted with chloroform. A mixture of diethyl ether and petroleum benzene was added to the extract to obtain 1.2 g of crystalline 8-cyclohexylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)-3,4-dihydrocarbostyril having a melting point of 148°-149° C. (after recrystallization from chloroform-n-hexane).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[O:14]=[C:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[C:16]([C:15](=[O:14])[CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)CCCCCCC(=O)O
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)CCCCCC(=O)O

Procedure:
The procedure described in Example 9 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.72 g of 8-ketononanoic acid. Yield 1.85 g (55%), yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@H:28]([CH3:32])[C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@:9]1([OH:19])[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]2[C@@H:10]1[CH2:11][N:12]([C:29](=[O:30])[C@H:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH3:20])[CH3:32])[CH2:13]2
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: COc1ccccc1C1(O)CC(C)CC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@H]2C[C@H](C)C[C@](O)(c3ccccc3OC)[C@H]2C1
Temperature: 5 °C
Yield: 36.1 %

Procedure:
To a solution of 1.54 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol in 150 cm3 of dichloromethane is added 1.0 cm3 of triethylamine. The reaction is mixture is cooled to 5° C. and 1.08 g of (S)-2(2-methoxyphenyl)propionic acid, 0.10 g of 1-hydroxybenzotriazole monohydrate and 1.26 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added. The reaction mixture is maintained for 1 hour at 5° C. and for 16 hours at 20° C. and is then washed twice with 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.060-0.200 mm, diameter 4 cm, height 70 cm), eluting under a pressure of 0.7 bar with a mixture of ethyl acetate and cyclohexane [by volume: 20/80 (2 dm3) then 30/70 (2 dm3) then 40/60 (2 dm3) and collecting 60 cm3 fractions. Fractions 57 to 72 are concentrated and, after drying at 40° C. at 15 Pa, 0.90 g of (3aR*,4R*,6S*,7aS*)-4-(2-methoxyphenyl)-2-[2-(S)-(2-methoxyphenyl)propionyl]-6-methyl-4-perhydroisoindolol is obtained in the form of a white solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:30])[CH3:29])[CH2:23]2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(N[C@H]2CCCN(C(=O)C)C2)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([N:24]1[CH2:25][CH2:26][CH2:27][C@H:22]([N:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:23]1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CCCN(C(C)=O)C2)s1
Agent: CC(=O)N1CCC[C@H](NC2CCCCC2)C1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)N1CCC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)C1

Procedure:
{2-[3-(1-Acetyl-piperidin-3(S)-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester prepared as described in general procedures (A) and (B). using 1-(3(S)cyclohexylamino-piperidin-1-yl)-ethanone and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11].N1C=CC=CC=1.O.[Cl:23][CH2:24]Cl>>[Cl:23][CH2:24][C:14]1[CH:13]=[CH:12][C:9]2[C:10]([CH3:11])=[C:6]([CH3:5])[O:7][C:8]=2[CH:15]=1
Reactant: ClCCl
Reactant: Cc1oc2ccccc2c1C
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1oc2cc(CCl)ccc2c1C
Yield: 76.4 %

Procedure:
Thionyl chloride (13.1 g, 0.11 mol) was added slowly to a stirred solution of 2,3-dimethylbenzofuran (18.0 g, 0.10 mol) and pyridine (8.3 cm3, 0.105 mol) in dichloromethane (170 cm3) at below 5° C., and the solution was heated under reflux for 3 hr. The solution was poured into water and separated, the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed to give 6-chloromethyl-2,3-dimethylbenzofuran (16.2 g, 0.078 mol, 76.4%). (Found: C, 67.76; H, 5.65; Cl, 18.21. C11H11ClO requires C, 67.87; H, 5.70; Cl, 18.22%) m.p. 63°-65° C. [ex petroleum ether (b.p. 60°-80° C.)].
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[CH:6][C:5]=1[N+:16]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[C:50]([O:53][CH2:54][CH2:55][Cl:56])[CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][CH2+:38]1SC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[C:50]([O:53][CH2:54][CH2:55][Cl:56])[CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][C:38]1=[N:16][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH:14]=[CH:15][C:4]=1[NH:3][CH2:1][CH3:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNc1ccc(NC(=O)COC)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-[5-(2-chloroethoxy)-3-methyl benzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 638 (M H+).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([N:10]=[S:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:25][C:26]([F:33])([F:32])[S:27]([O:30]C)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[F:25][C:26]([F:33])([F:32])[S:27]([O-:30])(=[O:29])=[O:28].[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7]([N:10]([S+:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:26])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)N=S(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N(C)[S+](c2ccccc2)c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 105.9 %

Procedure:
10.65 g (0.03 mol) of N-p-toluenesulfonyldiphenylsulfilimine were suspended in 50 ml of dry toluene and, after addition of 6.55 g (0.04 mol) of methyl trifluoromethanesulfonate, were stirred under reflux for 2 hours. On cooling, the reaction solution divided into two phases, the lower of which was removed. The solid residue remaining on concentrating the lower phase was recrystallized from ethyl acetate and dried to give 11.0 g of the salt (I). Analysis and properties are indicated in Table 1.
Reaction SMILES: [C-]#[N:2].[Na+].S(=O)(=O)(O)O.[C-]#N.[CH2:11]([C:13]([CH2:24][CH3:25])(O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12].[OH-].[Na+]>C(O)(=O)C>[CH2:11]([C:13]([NH2:2])([CH2:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12]
Reactant: CCC(O)(CC)Cc1ccc(OC)cc1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(N)(CC)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Powdered sodium cyanide (1.18 g, 24 mmol) was placed in a flask and covered with 5.5 mL of acetic acid. A mixture of sulfuric acid (3 mL) and acetic acid (2.75 mL) was cooled to 0° C. and then added to the cyanide suspension over a period of 3 minutes. The mixture was stirred for 30 minutes at room temperature, followed by the addition of 1,1-diethyl-2-(4-methoxyphenyl)ethanol (4.6 g, 22 mmol). The mixture was stirred overnight then poured into ice and sodium hydroxide. The product was extracted with ether, and the ether layer dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in 20% sodium hydroxide and refluxed overnight under nitrogen. The reaction was cooled, diluted with water, and extracted with ether. The ether layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (C-18 using 0.1% HCl/acetonitrile as the elutant) to give 1.91 g of 1,1-diethyl-2-(4-methoxyphenyl)ethylamine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1)=[O:11].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1)=[O:11])(=[O:4])=[O:3]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N)c3)ccc2C)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(NS(C)(=O)=O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
Methanesulphonyl chloride (0.25 g) was added to a stirred mixture of N-[5-(3-aminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.84 g), pyridine (0.5 ml) and methylene chloride (25 ml) and the mixture was stirred at ambient temperature for 48 hours. The mixture was washed with 2N hydrochloric acid and with water, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether and the resultant white solid was dried under vacuum at 60° C. There was thus obtained the title compound (0.85 g), m.p. >300° C.; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.03 (s, 3H), 3.82 (s, 6H), 7.06 (d, 1H), 7.23 (d, 1H), 7.4 (br d, 1H), 7.47 (t, 1H), 7.55 (br m, 2H), 7.63 (m, 1H), 7.66 (br d, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 9.73 (br s, 1H), 9.91 (br s, 1H), 10.24 (br s, 1H);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:15][C:16](=[O:26])[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N+:13]=[N-:14])=[CH:8][CH:7]=1.C([O:30][CH:31](OCC)[C:32]#[CH:33])C>O1CCOCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:15][C:16](=[O:26])[C:17]1[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=1[CH3:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:33]=[C:32]([CH:31]=[O:30])[N:14]=[N:13]2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(N=[N+]=[N-])cc1)NC(=O)c1c(C)cc(C)cc1C
Reactant: C#CC(OCC)OCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccc(-n2cc(C=O)nn2)cc1)NC(=O)c1c(C)cc(C)cc1C
Reaction time: 0.17 h

Procedure:
250 mg (0.68 mmol) of (13) and 684 μl (4.77 mmol) of 3,3-diethoxy-propyne were dissolved in 3 ml of dioxane. 500 μl of saturated Cu(AcO)2 solution in H2O were added and the solution was stirred for 10 min. After pouring in ethyl acetate the organic layer was washed with saturated NaHCO3, water, brine and dried over Na2SO4. The crude product was dissolved in 500 μl THF with 10% of HCl and stirred for 1 h. The solution was poured in 20 ml of saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2[S:21][C:20]3=[N:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:11]([OH:38])=[O:10])=[CH:17][CH:16]=4)=[CH:25][N:24]3[N:23]=2)=[CH:31][CH:30]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)OCC)cc4)nc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)O)cc4)nc3s2)cc1
Yield: 110.7 %

Procedure:
To a solution of 4-[2-(4-pentyloxyphenyl)imidazo-[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (5.2 g) in the mixture of methanol (104 ml) and tetrahydrofuran (52 ml) was added 2N NaOH aq. (47 ml) and refluxed for 36 hours. The reaction mixture was adjusted to pH 1-2 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[2-(4-pentyloxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (4.27 g).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[Cl:38]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:27][C:26]=2[Cl:38])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: NCCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.