Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:7][CH2:8][C:9](=O)[NH:10][N:11]=1.Cl[C:14]1[N:15]=[N:16]C(C2OC=CC=2)=C[CH:19]=1.C(NN)(=O)C>C(O)CCC>[CH3:19][C:14]1[N:10]2[N:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=[CH:8][C:9]2=[N:16][N:15]=1
Reactant: Clc1ccc(-c2ccco2)nn1
Reactant: O=C1CCC(c2ccco2)=NN1
Agent: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccco3)nn12

Procedure:
As for Example 5, 4,5-dihydro-6-(2-furyl)-3(2H)-pyridazinone is converted to 3-chloro-6-(2-furyl)pyridazine. A 1.5 g. sample of the preceding compound, 1.2 g. of acethydrazide in 50 ml. of n-butyl alcohol is refluxed for 48 hours. The solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and dilute sodium hydroxide. The dichloromethane layer is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by conventional means to give the product of the Example.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:11].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([Br:11])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c(Br)c1
Yield: 97 %

Procedure:
A mixture of 87.6 g (0.38 mole) of 95% pure 4-fluoro-3-bromo-benzoic acid, 200 ml of methanol and 3 ml of sulphuric acid was boiled under for 18 hours. The excess methanol was then distilled off in vacuo, 300 ml of toluene were added and the solution was shaken first with 50 ml of water, then with 50 ml of saturated sodium bicarbonate solution and subsequently with 50 ml of water again. Thereafter, the solvent was distilled off in vacuo and the residue was distilled in vacuo. 86 g (97% of theory) of 4-fluoro-3-bromo-benzoic acid methyl ester were obtained in this manner in the form of a colorless oil which solidified as crystals when cold and had a boiling point of 64° C./0.1 mm Hg.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([S:13]([N:16]([CH2:18][P:19](=[O:22])([OH:21])[OH:20])[CH3:17])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.Cl>O>[NH2:4][C:5]1[CH:6]=[C:7]([S:13]([N:16]([CH2:18][P:19](=[O:20])([OH:21])[OH:22])[CH3:17])(=[O:14])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(S(=O)(=O)N(C)CP(=O)(O)O)cc1NC(C)=O
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N(C)CP(=O)(O)O)cc1N
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A portion of the paste (693 parts) from (a) was added at 60°-90° C. to a mixture of 232.5 parts of water and 270 parts of concentrated hydrochloric acid, heated to 95° C. and held at this temperature for 1 hour. Addition of 700 parts of ice cooled the solution to 20° C. Upon stirring or standing for 24 hours crystals of N-(3'-amino-4'-methoxyphenylsulfonyl)-N-methylaminomethylphosphonic acid formed which melted at 218°-220° C. The hydrolysis solution, after cooling with ice, was used directly for synthesis of dyes; isolation of the product was not necessary.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:22](C)=O.[Na+]>C(Cl)Cl.CO>[CH3:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[N:10]=[CH:9][N:8]=2)[CH2:2][CH2:3]1
Reactant: c1nc(-c2ccsc2)nc(N2CCNCC2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ncnc(-c3ccsc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-piperazin-1-yl-4-thiophen-3-yl-[1,3,5]triazine (0.17 mmol) in CH2Cl2/MeOH (3:1, 4 mL) was added formaldehyde (37 wt. % in water, 22 mg, 0.26 mmol). After stirring for 1 h at room temperature, NaB(OAc)3H (72.8 mg, 0.34 mmol) was added. The reaction mixture was stirred overnight at room temperature, then quenched with 1 N NaOH (3 mL), and extracted with EtOAc (50 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried, and concentrated to yield a light yellow oil.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][O:35]2)(=O)=O)=CC=1.[I-].[K+].Cl>CN(C)C=O>[O:35]1[CH2:36][CH2:37][CH2:38][C@@H:34]1[CH2:33][N:11]1[C:12]2[CH:13]=[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]3=[CH:7][C:8]=2[C:9](=[O:15])[C:10]1=[O:14]
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C[C@H]2CCCO2)c2cc3c(cc21)OCCO3
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a stirred solution of 2H-[1,4]dioxino[2,3-f]indole-7,8(3H,6H)-dione (2.05 g, 10.0 mmol) in dry N,N-dimethylformamide (100 mL) was added cesium carbonate (4.4 g, 12.0 mmol) at ambient temperature. The dark mixture was stirred for 1 h, followed by the addition of (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (3.07 g, 12.0 mmol) in one portion and potassium iodide (0.66 g, 4.0 mmol). The dark mixture was stirred at 70° C. for 16 h. The mixture was poured into 5% hydrochloric acid solution (300 mL) and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography with ethyl acetate in hexanes (30 to 50% gradient) to afford 6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (0.59 g, 20%): MS (ES+) m/z 290.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20](O)=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:31][NH2:32]>O1CCCC1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20]([NH:32][CH3:31])=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: O=C(O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
To a solution of (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-carboxyethyl)-4-hydroxypyrrolidine (57.73 g) in dry tetrahydrofuran (500 ml), triethylamine (29.27 ml) was added, and ethyl chloroformate (18.74 ml) was further added thereto at -20° to -25° C. under nitrogen stream. The resulting mixture was stirred at the same temperature for 15 minutes and 30% (w/w) ethanolic solution of methylamine (57.5 g) was added thereto, followed by stirring at the same temperature for 1 hour. The solvent was removed, and the residue was combined with water and ether. The precipitated crystals were collected by filtration to give (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-methylaminocarbonylethyl)-4-hydroxypyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH2:19]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23]C(OCC)=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH2:19][Cl:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncc(C#N)cc12
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cc(C#N)cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (634, 2.60 g, 8.66 mmol) in toluene (60.0 mL) under an atmosphere of nitrogen was added ethyl chloroformate (0.828 mL, 8.66 mmol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (635, 400 mg, 16%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:29][CH2:28]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)n(C(C)(C)C)n1

Procedure:
171 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(4-chlorophenyl)piperazine (121 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:20][N:21]([CH3:29])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1O.[I-].[K+]>O.O1CCCC1.C1(C)C=CC=CC=1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[N:21]([CH3:29])[CH3:20]
Reactant: CN(C)C1CCCCC1O
Reactant: CN(C)CCO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOC1CCCCC1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To tetrahydrofuran (100 mL), oily sodium hydride (purity 60% by weight, 18 g, 450 mmol) was added and 2-(dimethylamino)ethanol (16.1 g, 180 mmol) was added dropwise at 0° C., and then the mixture was refluxed for 3 hours. To this suspension, toluene (80 mL) and tetrahydrofuran (25 mL) were added. A toluene (200 mL)/tetrahydrofuran (25 mL) mixed solution of p-toluenesulfonyl chloride (37.2 g, 195 mmol) was added dropwise at 0 to 5° C., followed by stirring at the same temperature for 1 hour. After further stirring for 1 hour under heating at reflux, the mixture was left standing to cool to room temperature. After adding dropwise 2-(dimethylamino)cyclohexanol (21.5 g, 150 mmol) at room temperature, potassium iodide (29.9 g, 180 mmol) was added. After stirring for 9 hours under heating at reflux, the reaction solution was left standing to cool to room temperature. Water was added and the solution was extracted with ethyl acetate, and then the organic phase was washed with water and saturated saline. This organic phase was dried over an anhydrous magnesium sulfate powder and then concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 2.3 g (in a yield of 7%) of the objective compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:7][CH:2]1[C:3](=[O:9])[NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9]1
Reactant: Cc1ccc(O)c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)NC(=O)C(C)O2
Reaction time: 4 h
Yield: 43 %

Procedure:
3.39 g of 2-amino-4-methylphenol is mixed in 12 ml of toluene with 1.8 g of sodium hydride, and 3.95 ml of 2-bromo-propionic acid ethyl ether is added drop by drop at ice bath temperature. After 4 hours at room temperature, it is poured onto water, extracted with ethyl acetate, washed with brine, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Column chromatography with hexane/ethyl acetate yields 43% product.
Reaction SMILES: [O-]S([C:5](F)(F)F)(=O)=O.FC1C=CC(B(O)O)=CC=1.[CH:19]1([N:24]2[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[C:32]3[C:26]([CH2:27][CH2:28][NH:29][CH:30](C)[CH2:31]3)=[N:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([N:24]2[C:33]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[C:32]3[C:26]([CH2:27][CH:28]([CH3:5])[NH:29][CH2:30][CH2:31]3)=[N:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC1Cc2c(nn(C3CCCC3)c2-c2ccc(F)cc2)CCN1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: OB(O)c1ccc(F)cc1
Product: CC1Cc2nn(C3CCCC3)c(-c3ccc(F)cc3)c2CCN1

Procedure:
The title compound (160.4 mg) was prepared as in Example 263 from 301 mg of the triflate from Step B and 185 mg of 4-fluorophenylboronic acid. The sequence also produced 2-cyclopentyl-3-(4-fluoro-phenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. The isomers were separated by SFC chromatography. MS (ESI): exact mass calculated for C19H24FN3, 313.41. found, m/z 314.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.25-7.21 (m, 2H), 7.18-7.12 (m, 2H), 4.22 (m, 1H), 3.24-3.18 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.67 (m, 2H), 2.60-2.52 (m, 1H), 2.45-2.39 (m, 1H), 2.16-1.82 (m 6H), 1.59-1.47 (m, 2H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]=1.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([C:20]#[C:19][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:33][CH:34]=2)[CH:11]=[CH:10]3)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccc3nc(C#Cc4ccc(OCCN5CCCC5)cc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a nitrogen atmosphere, 0.6 mg CuI, 9.3 mg Pd(PPh3)2Cl2 and 318 mg (1 mmol) 2-bromo-6-(4-chloro-phenyl)-quinoline are added successively to a solution of 142 mg (0.66 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine and 2.6 mL (18.67 mmol) triethylamine in 5 mL absolute DMF and 10 mL acetonitrile. The reaction mixture is stirred for 14 h at RT and evaporated down. The purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 90:10:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([C:17]([OH:19])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:24]O>>[CH3:24][O:18][C:17]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1)=[O:19]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc([N+](=O)[O-])c2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (10.00 g, 0.039 mol) in methanol was added SOCl2 (5.09 g, 0.043 mol) at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to reflux for 2 hours. The solvent was removed in vacuo to afford 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester (9.72 g, 92%) as light yellow solid. MS (M+H)=273.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.ClCCCl>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]2[CH2:18][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[CH2:20]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
0.73 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (b) above] was dissolved in 1.53 ml of anisole, and 7.25 ml of trifluoroacetic acid and 0.25 ml of trifluoromethanebulfonic acid were added dropwise, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 90 minutes, after which 1,2-dichloroethane was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. The resulting residue was washed by repeated decantation, in turn, with hexane and with diethyl ether. The residue was diluted with ethyl acetate and was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was washed with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 420 mg of the title compound, in the form of an amorphous powder.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:10]=[C:9]1[CH2:25][O:26]CC1C=CC(OC)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[C:12]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:10]=[C:9]1[CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2Cc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)c1nc(CO)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 91.9 %

Procedure:
To 25 ml of methanol was dissolved 1.41 g (2.67 mmol)of 1-benzyl-5-(3,5-dichlorophenylthio )-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17f), followed by addition of 12.5 ml of 6N-hydrochloric acid at room temperature with stirring, and the mixture was stirred under heating at 60° C. for 3 hour. This reaction mixture was concentrated under reduced pressure, the residual solution was neutralized with a saturated aqueous solution of sodium bicarbonate to be weakly basic, and was extracted with methylene chloride. The extract was rinsed with water, and then, was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was crystalized from n-hexane and collected by filtration to give 1.0 g (yield 92%)of [1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-2-yl]methanol (Compound I-16). mp 121-124° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[S:42])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccccc32)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=S)C2CCCc3ccccc32)cc1
Yield: 23.2 %

Procedure:
To a solution of N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.79 g) in toluene (10 mL) was added Lawesson's reagent (0.9 g), and the mixture was heated under reflux for 5 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carbothioamide (0.19 g). melting point: 123-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[NH:8]C(=O)C.Cl.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-chloro-4-acetamidophenylacetic acid (180 grams, 0.79 moles) in methanol (2 L), was treated with concentrated HCl (200 mL) and the resulting solution refluxed for 6 hours and then stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to about one-half its volume and ether (4 L) was added. The resulting precipitate was filtered, washed with ether and dried to give the title compound (173 grams) as a tan solid NMR, (CD3OD): δ3.70 (s, 2H); 3.73 (s, 3H); 7.35 (d, 1H); 7.43 (d, 1H); 7.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:16]=[CH:15][N:14]=[CH:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCCCCCCn1ccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(NCCCCCCCCn1ccnc1)c1ccc(Cl)cc1

Procedure:
The compound of this Example, mp 54°-56° C., was obtained when 4-chlorobenzenesulfonyl chloride was reacted with 1H-imidazole-1-octanamine by the procedure of Example 20.
Reaction SMILES: S(=O)(=O)=O.[CH2:5]1S(=O)(=O)O[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:6]1>>[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCC1CCCS(=O)(=O)O1
Agent: O=S(=O)=O
Product: C=CCCCCCCCCCCCCCCCCCCCC

Procedure:
The sultones were the pure compounds derived by sulphur trioxide reaction with straight chain alpha-olefins, except that the delta-docosane sultone was a mixture mostly in the delta form and obtained by the sulphonation of docos-1-ene dissolved in light petroleum (b.p. 60°-80°) with sulphur trioxide vapour and nitrogen at 50° using a 20% molar excess sulphur trioxide for 1 hour and allowing the reaction mixture to age for 4 hours at 60° in order to allow isomerisation to delta-sultone, followed by filtration and recrystallisation of the sultone residue from methanol and finally from hexane.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:26][C@@:24]2([CH3:25])[C@@H:20]([CH2:21][CH2:22][C@@H:23]2[OH:27])[C@@:19]2([CH:28]=[CH2:29])[C@H:10]1[C:11]1[CH:12]=[CH:13][C:14]([OH:30])=[CH:15][C:16]=1[CH2:17][CH2:18]2>>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:26][C@@:24]2([CH3:25])[C@@H:20]([CH2:21][CH2:22][C@@H:23]2[OH:27])[C@@:19]2([CH:28]=[CH2:29])[C@H:10]1[C:11]1[CH:12]=[CH:13][C:14]([OH:30])=[CH:15][C:16]=1[CH2:17][CH2:18]2
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCBr)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: CN
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCNC)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with methylamine (40% in water, 2 ml/mmol) analogously to instructions 17.2, 258 mg of bromide 30a yields 161 mg of amine 31a as a colorless solid (GC-MS: m/z theor.: 397, pract.: 397).