Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20].[C:21]1([Se:27]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([Se:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:20]
Reactant: CN1CCCCC1=O
Reactant: Cl[Se]c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1CCCC([Se]c2ccccc2)C1=O
Reaction time: 0.08 h

Procedure:
A solution of diisopropylamine (3.02 mL, 21.21 mmol) in tetrahydrofuran (44.2 mL) under argon was cooled to −78° C. and added butyllithium solution, 2.5M in hexanes (8.48 mL, 21.21 mmol). After 5 min, a solution of 1-methylpiperidin-2-one (2 g, 17.67 mmol) in tetrahydrofuran (2 mL) was added dropwise. After stirring for 10 min, a solution of phenylselenenyl chloride (4.06 g, 21.21 mmol) in 16 mL of tetrahydrofuran was added, and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with aqueous saturated NH4Cl solution and diluted with CH2Cl2; the aqueous layer was back-extracted with CH2Cl2 (1×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford a crude crop of 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane. To the crude 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane (50 mL) at 0° C. under argon was added 3-chlorobenzoperoxoic acid (7.92 g, 35.3 mmol). The resulting mixture was allowed to gradually warm to room temperature overnight. The orange suspension was filtered, and the filtrate was concentrated in vacuo and partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (5×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methyl-5,6-dihydropyridin-2(1H)-one (1.33 g, 67.7% yield) as a brown oil. [M+1]=112.2.
Reaction SMILES: [Na].Cl[C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>CO.[Cu]>[Cl:12][C:9]1[CH:8]=[C:4]([C:3]([O:19][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[CH:13]=2)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(O)c1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [Cu]
Agent: [Na]
Solvent: CO
Product: Cc1cccc(Oc2ccc(Cl)cc2C(=O)O)c1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Sodium (2.41 g) was dissolved in methanol and the solution placed under dry oxygen-free nitrogen. 2,5-Dichlorobenzoic acid (10 g), m-cresol (30 g) and activated copper powder (0.5 g) were added and the methanol removed by distillation. The temperature was increased to 180° with vigorous stirring and this temperature was maintained for 3 hours. The solution was cooled and steam distilled to remove the excess phenol. The resulting solution was filtered, cooled to room temperature and acidified with hydrochloric acid to give an oil. The oil slowly solidified; it was filtered off, dried, and washed with petroleum ether (30°-40° ). It was recrystallised at -10° from diethyl ether/petroleum ether (30°-40° ) to give, as a grey solid, the title compound (4.5 g), mp 124°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC(CCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
A solution of 50 g of 3,4-difluorophenyl acetonitrile in 50 ml of THF is added dropwise at 20° C. to a suspension of 14.4 g of 60% sodium hydride in oil in 250 ml of THF, and the reaction mixture is left stirring for three hours at RT. It is cooled in an ice bath, a solution of 68.2 g of 1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 50 ml of THF is added dropwise and the reaction mixture is left stirring overnight at RT. It is acidified by adding a pH 2 buffer solution, and the THF is then evaporated off under vacuum. The aqueous phase is extracted with ether, the organic phase is washed twice with a pH 4 buffer solution, with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with toluene and then with a toluene/AcOEt (100:3; v/v) mixture. 50 g of the expected product are obtained.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=NC=1.[NH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:51]=[C:50]3[C:46]([CH2:47][N:48]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[C:49]3=[O:52])=[CH:45][CH:44]=2)=[N:41][CH:42]=1.[F:61][C:62]1[CH:63]=[C:64]([N:69]=[C:70]=[O:71])[CH:65]=[CH:66][C:67]=1[F:68]>>[F:61][C:62]1[CH:63]=[C:64]([NH:69][C:70](=[O:71])[NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:51]=[C:50]4[C:46]([CH2:47][N:48]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[C:49]4=[O:52])=[CH:45][CH:44]=3)=[N:41][CH:42]=2)[CH:65]=[CH:66][C:67]=1[F:68]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cn3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 399 was prepared analogous to the compound of example 393 by reaction of the compound of example 392 with 3,4-difluoro phenyl isocyanate.
Reaction SMILES: [NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17])[CH2:3][CH3:4].[OH-].[Na+].[CH3:25]I>CC(C)=O.O>[NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16](=[N:18][C:19]([O:21][CH3:22])=[O:20])[S:17][CH3:25])[CH2:3][CH3:4]
Reactant: CCCSc1ccc(C(=N)CC)c(NC(=S)NC(=O)OC)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCSc1ccc(C(=N)CC)c(NC(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a suspension of 1-iminopropyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (1 g.; 0.00295 mole) in acetone (30 ml.) and water (15 ml.) there is added 50.8% aqueous sodium hydroxide (0.23 g.; 0.00295 mole). The solution that forms is stirred at room temperature for one hour and to it there is added methyl iodide (0.42 g.; 0.00295 mole). The turbid solution formed is stirred at room temperature for 30 minutes and is poured into water (500 ml.). The suspension formed is stirred at room temperature for one hour and is vacuum filtered. The filter cake is dried to afford 1-iminopropyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (0.85 g.; 81.5%), m.p. 85°-90° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.C(Cl)Cl.C(N(CC)CC)C.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[NH:8][CH2:9][CH2:10][N:11]([S:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:12]1
Reactant: COc1cccc(CC2CNCCN2)c1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a 100-mL round-bottomed flask was added 2-(3-methoxybenzyl)piperazine (128 mg, 0.62 mmol), 5 mL of CH2Cl2, triethylamine (0.129 mL, 0.93 mmol) and 2-thiophenesulfonyl chloride (0.113 mL, 0.62 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was stirred at 0° C. for 1 h and then diluted with aqueous saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 5% MeOH in EtOAc to give 3-(3-methoxybenzyl)-1-(thiophen-2-ylsulfonyl)piperazine as a colorless oil (162 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1([CH3:24])[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:24][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=2)=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 84.3 %

Procedure:
A solution of 8.0 g (49.65 mmoles) of 4-aminobenzotrifluoride in 10 ml of methylene chloride was added to a solution of 9.85 g (49.95 mmoles) of p-toluenesulfonyl isocyanate in 75 ml of methylene chloride with stirring. The mixture became quite warm and a heavy white precipitate formed. An additional 100 ml of methylene chloride were added. The reaction mixture was stirred an additional 15 minutes, and the precipitate was recovered by filtration affording 15.0 g of the title product as a white solid. A small amount of the material was crystallized from diethyl ether to provide the title compound (87% yield) with a melting point of 194-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)(=[O:20])=[O:19]
Reactant: OCc1ccnc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
To a stirred solution of (2-chloropyridin-4-yl)methanol (0.500 g, 3.496 mmol) in dichloromethane (15 mL), triethylamine (0.424 g, 4.195 mmol) and methanesulfonylchloride (0.440 g, 3.846 mmol) were added at 0° C. and stirred at room temperature for 2-3 h. The reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated in vacuo to give (2-chloropyridin-4-yl)methyl methanesulfonate (0.530 g, 68%); MS: 221.9 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH2:13]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][C@@H:22]1Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([C@@H:22]3[O:23][C@H:24]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:21]3[O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A suspension of 240 mg of sodium hydride, 1.54 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, and 6 ml of dry dimethylformamide (DMF) is stirred at 50° C. for 15 minutes, cooled, and added to 4.83 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride in 4 ml of DMF. The solution is stirred at ambient temperature for two hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate-water. Chromatography of the dried ethyl acetate layer over silica gel with 4:1 benzene-ethyl acetate provides 3.3 g of yellow, syrupy 4-chloro-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: BrC1C=C[C:5]([O:8]C(F)(F)F)=[CH:4]C=1.[Mg].II.[N:16]1[N:17]([CH:21]([CH3:34])[C:22](C2C=CC(C(F)(F)F)=CC=2)=[O:23])[N:18]=[N:19][CH:20]=1.Cl>O1CCCC1.O>[CH2:5]([O:8][C:22](=[O:23])[CH:21]([N:17]1[N:18]=[N:19][CH:20]=[N:16]1)[CH3:34])[CH3:4]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C(=O)c1ccc(C(F)(F)F)cc1)n1ncnn1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)n1ncnn1
Reaction time: 1 h

Procedure:
The Grignard reagent from 4-bromotrifluoromethoxybenzene (2.41 g) was prepared in a similar manner to that described in Example 3 from magnesium turnings (0.24) in dry tetrahydrofuran (14 ml) with iodine (1 crystal) as an activator. To the Grignard solution was added dropwise over 10 minutes 2-(2H-tetrazol-2-yl)p-trifluoromethylpropiophenone from Example 16 (2.7 g in dry tetrahydrofuran (10 ml), then the reaction stirred for 1 hour. The reaction was worked up as for previous examples, by pouring into water, acidifying with aqueous hydrochloric acid and extracting the product into diethyl ether, which was dried over anhydrous sodium sulphate and evaporated. The residual oil (4.3 g) was purified by h.p.l.c. on silica gel eluting with 5:1 hexane/ethyl acetate to give a colourless oil 2.3 g.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[NH:37][CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1.[C:48]([O:52][C:53]([N:55]1[CH2:58][CH:57]([C:59](O)=[O:60])[CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[N:37]([C:59]([CH:57]4[CH2:58][N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH2:56]4)=[O:60])[CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC3CN(Cc4ccc(F)cc4)CCN3c3ncccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of the product of Example 64C (97 mg, 0.31 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (94 mg, 0.465 mmol) in CH2Cl2 (2 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was applied directly to a column of silica gel and eluted with 5% methanol-CH2Cl2 to provide the title compound: MS (DCI) m/z 496 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:20]1([C:23]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.[S].C(O)(=O)C>C(O)C>[CH:20]1([C:23]2[N:28]=[C:27]([C:29]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Reactant: O=Cc1cccc(C2CC2)n1
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate (250 mg, 0.686 mmol) in ethanol (15 mL) was added 6-cyclopropylpicolinaldehyde (55 mg, 0.823 mmol), sulfur (43 mg, 1.372 mmol) and acetic acid (1.5 mL) at room temperature. The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organics were concentrated under reduced pressure and the crude material was purified via preparative TLC (80% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(6-cyclopropylpyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (180 mg). MS (ES+APCI) (M+H) 392.2; LCMS retention time 3.757 min (Method J).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[CH:25]([O:24][CH2:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COCCOCOc1ccc(C=CC(=O)NCCCOC(c2ccccc2)c2ccccc2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)NCCCOC(c2ccccc2)c2ccccc2)ccc1O
Yield: 73.3 %

Procedure:
To a solution of 378 mg (0.75 mmol) of the amide compound in methanol (10 ml) was added 19 mg (0.1 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was heated and refluxed for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, which .was extracted with ethyl acetate, and the organic layer was concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform - methanol (50 : 1), to give 230 mg (0.55 mmol) of 3-[3-[3-methoxy-4-hydroxyphenyl)-2-propenoyl]aminopropyl benzhydryl ether. Spectrophotometric data of the product support the structure shown below. ##STR86##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[H-].[Na+].N1(P(Cl)(N2CCOCC2)=O)CCOCC1.[C:37]([NH:40][NH2:41])(=O)[CH3:38]>O1CCCC1.C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:37]([CH3:38])=[N:40][N:41]=[C:10]3[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CC(=O)NN
Reactant: O=C1CC=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: O=P(Cl)(N1CCOCC1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.075 g of 7-chloro-5-phenyl-1,3-dihydro-2H-1-benzazepin-2-one in 20 ml of dry tetrahydrofuran is treated with 0.23 g of sodium hydride (50% dispersion in mineral oil) and stirred at 60° for 1 hour. The mixture is then cooled to room temperature, treated with 1.53 g of bis-(4-morpholinyl)phosphinic acid chloride and stirred at this temperature for a further 2 hours. A solution of 0.593 g of acetic acid hydrazide in 50 ml of n-butanol is subsequently added thereto, the mixture is heated to boiling under reflux for 1 hour and then evaporated in vacuo. The residue is partitioned between water and methylene chloride. The methylene chloride solution is evaporated and the residue is chromatographed on 100 g of aluminium oxide (activity grade III). Various impurities and starting material are eluted successively with benzene and ethyl acetate/hexane (1:1). After elution with chloroform/ethanol (96:4) and recrystallization of the crude product from ethyl acetate/benzene/n-hexane, there is obtained 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1]benzazepine of melting point 235°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:17])[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:18][OH:19].[Mn]([O-])(=O)(=O)=[O:21].[K+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:17])[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:5]=2[N:4]=[C:3]1[C:18]([OH:21])=[O:19]
Reactant: CCCCC(=O)c1cc2nc(CO)n(C)c2cc1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1C

Procedure:
In a manner analogous to that described in Example 12, 4.7 g of 1,6-dimethyl-5-valeryl-benzimidazole-2-methanol are oxidised with 4.5 g of potassium permanganate to give 1,6-dimethyl-5-valeryl-benzimidazole-2-carboxylic acid with a melting point >88° (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:16][CH3:17])=[CH:11][C:12]([CH3:15])=[C:13]([Br:18])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C)ccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1cc(C)c(Br)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
4-benzyloxy-3-methoxytoluene (8.0 g) was dissolved in dimethylformamide (30 ml and a dimethylformamide (15 ml) solution of N-bromosuccinimide (6.36 g) was dropwise added thereto, followed by stirring at room temperature for one night. The reaction solution was poured into ice water (400 ml), and crystals thus deposited were collected by filtration, adequately washed with water, and dried for one night to obtain 10.64 g of 4-benzyloxy-2-bromo-5-methoxytoluene (m.p. 110-111° C.) substantially quantitatively, and its structure was confirmed by nuclear magnetic resonance spectrum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[NH2:38])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[NH:38][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-2-(3-fluorophenyl)-3-methylquinoline (127 mg, 467 μmol), 2,5-dimorpholinobenzenamine (123 mg, 467 μmol) and 4N hydrochloric acid solution in dioxane (0.12 mL, 467 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.0, 1.0 Hz), 7.66-7.75 (1H, m), 7.43-7.56 (2H, m), 7.32-7.43 (2H, m), 7.25 (1H, s), 7.07-7.22 (2H, m), 6.45 (1H, dd, J=8.6, 2.7 Hz), 6.03 (1H, d, J=2.7 Hz), 3.88-3.99 (4H, m), 3.67-3.80 (4H, m), 3.01-3.14 (4H, m), 2.88-2.99 (4H, m), 2.32 (3H, s). Mass Spectrum (ESI) m/e=499.1 (M+1).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1.[CH3:34][C:35]#[N:36]>>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:33][C:35]([CH3:34])=[N:36][CH:32]=2)=[CH:27][CH:26]=1
Reactant: CC#N
Reactant: CC(=O)c1ccc(Br)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: Cc1ncc(-c2ccc(Br)cc2)o1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic acid (6.6 ml) was added to a flask containing iodobenzene diacetate (12.2 g) and MeCN (200 ml) at rt. After 25 min. a solution of 4′-bromoacetophenone (5 g) in MeCN (50 ml) was added and the resultant mixture heated at reflux for 6 h. The reaction was allowed to cool to rt before the solvent was evaporated and the residue partitioned between saturated aqueous Na2CO3 (150 ml) and EtOAc (150 ml). The organic phase was washed with saturated brine (150 ml), dried (MgSO4) and evaporated to give an orange solid. The crude product was purified by column chromatography (silica gel, 50% EtOAc in hexane) to give the title compound (D38) as a pale yellow solid (3.5 g). LCMS electrospray (+ve) 239 (MH+).