Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=O
Yield: 84.6 %

Procedure:
At reflux temperature, a solution of 5.00 g (0.018 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate was added dropwise to a solution of 9.60 g (0.072 mol) of lithium iodide and 70 ml of dry pyridine. After stirring under reflux for 2 hours, the reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was then taken up in water and adjusted to pH 1-2 with dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water until neutral, dried and concentrated. 4.00 g of 2-chloro-3-formyl-4-methylsulfonylbenzoic acid (85% yield) were obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2.5 h
Yield: 16.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), anhydrous piperazine (180 mg) and anhydrous dimethyl sulfoxide (DMSO; 3 ml) was stirred for 2.5 hours at 70° to 80° C. on an oil bath. The reacting mixture was concentrated under reduced pressure and cold water was added to the residue. The precipitate was collected by filtration and recrystallized from a mixed solution of dichloromethane-methanol (1:1) to give the title compound (40 mg) as pale yellow prisms, mp 187° C. (decompd.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH2:15])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+].O.N>Br>[NH2:15][C@H:11]1[CH2:12][CH2:13][CH2:14][C@H:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH2:10]1
Reactant: COc1cccc([C@H]2CCC[C@H](N)C2)c1
Agent: Br
Agent: N
Agent: O=C([O-])O
Solvent: O
Product: N[C@H]1CCC[C@H](c2cccc(O)c2)C1
Yield: 65.8 %

Procedure:
47% Hydrobromic acid (140 ml) was gradually added to (trans)-3-(3-methoxyphenyl) cyclohexylamine (14.0 g) and the mixture was refluxed for an hour. After adjusting the reaction solution to pH7 with sodium bicarbonate (powder), it was adjusted to pH9 with concentrated ammonia water. After filtering the deposited crystals by suction and washing with water, they were dried by ventilation at 45° C. for 5 hours to give 8.58 g of (trans)-3-(3-aminocyclohexyl)phenol (65.8% yield).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.O=P(Cl)(Cl)[Cl:17].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc2oc(=O)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccc2oc(=O)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A stirred mixture of 4-hydroxy-6-methoxycoumarin (116 g, 0.603 mole) and POCl3 (462.29 g, 3.015 mole) in toluene is treated dropwise with tri-n-butylamine (250 mL, 1.73 mole) at 25° C., heated at 100°-110° C. and monitored by HPLC analysis. When the reaction is complete, the mixture is cooled to room temperature, poured over ice, stirred mechanically for about 2 hours and filtered. The filtercake is washed with water and toluene, dissolved in methylene chloride and filtered through diatomnaceous earth. The methylene chloride filtrate is concentrated and treated with a mixture of dimethylformamide and acetonitrile to afford crystallization. The mixture is filtered to give the title product, 81.7 g, (64% yield) identified by HPLC analysis.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.Cl[CH2:23][CH2:24][N:25]([CH2:33][CH2:34]Cl)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].Cl>O1CCCC1>[Br:11][C:12]1[CH:20]=[C:19]2[NH:18][C:17](=[O:21])[C:16]3([CH2:34][CH2:33][N:25]([C:26]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:32])[CH2:24][CH2:23]3)[C:15]2=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 2.80 mL, 2.80 mmol) was added dropwise to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 0.20 g, 0.94 mmol) in tetrahydrofuran (1.5 mL) at 0° C. The mixture was stirred for 15 minutes, then tert-butyl bis(2-chloroethyl)carbamate (0.25 g, 1.04 mmol) in THF (1 mL) was added dropwise and the mixture was warmed to room temperature. After stirring overnight, 2M aqueous hydrochloric acid was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (5:1 hexanes/ethyl acetate) gave the title compound (0.08 g, 22%) as a yellow solid.
Reaction SMILES: O.NN.[S:4]1[C:8]2[CH:9]=[C:10]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:12][C:7]=2[N:6]=C1.C(N(CC)CC)C.[CH3:26][O:27][C:28](=[O:34])[CH2:29][C:30](=O)[CH2:31]Cl>C(O)C.O1CCCC1>[CH3:26][O:27][C:28](=[O:34])[CH2:29][C:30]1[NH:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH3:18])=[CH:9][C:8]=2[S:4][CH:31]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: CN(c1ccc2ncsc2c1)S(C)(=O)=O
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)CC1=CSc2cc(N(C)S(C)(=O)=O)ccc2N1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
Hydrazine monohydrate (20.1 mL, 414 mmol) was added to a solution of N-benzothiazol-6-yl-N-methyl-methanesulfonamide (Example 7b, 10.06 g, 41.5 mmol) in ethanol (150 mL) at 25° C. The reaction mixture was heated to 50° C. for 13 h, and then was concentrated in vacuo. The residue was dissolved in 1.0 M aqueous hydrochloric acid solution (100 mL) and the pH was adjusted to 7 by the addition of 6.0 M aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate (2×150 mL) and the aqueous layer was acidified to pH 3 by the addition of 6.0 M aqueous hydrochloric acid solution, and then neutralized to pH 7 by the addition of solid sodium bicarbonate. The mixture was again extracted with ethyl acetate (1×150 mL) and all organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The orange solid thus obtained was dissolved in tetrahydrofuran (150 mL) and triethylamine (12.3 mL, 88.2 mmol), and 4-chloro-3-oxo-butyric acid methyl ester (5.10 mL, 44.2 mmol) were added sequentially at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 20→100% ethyl acetate in hexanes) afforded the desired product, [7-(methanesulfonyl-methyl-amino)-4H-benzo[1,4]thiazin-3-yl]-acetic acid methyl ester (8.40 g, 25.6 mmol, 64% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.86 (3H, s), 3.27 (3H, s), 3.43 (2H, s), 3.72 (3H, s), 6.86 (1H, d, J=8.6 Hz), 7.12 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.21 (1H, d, J=2.4 Hz), 10.63 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)cccc2OC)c(N)n1
Product: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,6-dimethoxyphenyl)-methanone (Example 333) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(2,6-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 400.
Reaction SMILES: Br[CH:2]([CH:8]=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]([NH2:13])=[O:12]>CN(C=O)C>[NH2:13][C:11]1[O:12][C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:8][N:10]=1
Reactant: COC(=O)CC(Br)C=O
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cnc(N)o1
Temperature: 110 °C
Yield: 18 %

Procedure:
A 250-mL round bottom flask was charged with methyl 3-bromo-4-oxobutanoate (5.00 g, 25.6 mmol) and urea (2.08 g, 34.6 mmol) in DMF (15 mL) and heated to 110° C. for 30 minutes. After this time, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was absorbed onto silica and purified by chromatography on silica using dichloromethane/(89:9:1 dichloromethane/methane/conc. NH4OH) (10:0 to 0:10) as eluent, to afford the title compound (0.72 g, 18%) as a red oil. MW=156.14. 1H NMR (DMSO-d6, 300 MHz) δ 9.54 (s, 1H), 6.48 (s, 2H), 6.45 (s, 1H), 3.64 (s, 2H), 3.62 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([O:10][CH3:11])[CH2:8][S:9][C@H:4]12.[C:27]([O:31][C:32]([CH2:34][O:35][N:36]=[C:37]([C:41]1[N:42]=[C:43]([NH:46][CH:47]=[O:48])[S:44][CH:45]=1)[C:38](O)=[O:39])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([CH2:34][O:35][N:36]=[C:37]([C:41]1[N:42]=[C:43]([NH:46][CH:47]=[O:48])[S:44][CH:45]=1)[C:38]([NH:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:7]([O:10][CH3:11])[CH2:8][S:9][C@H:4]12)=[O:39])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 100.4 %

Procedure:
4-Nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate hydrochloride (4.02 g) and 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer, 3.62 g) were treated in a similar manner to to that of Example 1 to give 4-nitrobenzyl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 6.8 g).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>CN(C=O)C.CCOC(C)=O>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([N:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH3:30])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (8) (6.27 g, 33.5 mmol) in DCM (100 mL) was added DIEA (8.75 mL, 50.3 mmol) and then 4-tert-butylbenzoyl chloride (8.0 mL, 43.6 mmol) in drop-wise manner. The mixture was stirred for 3 h at RT, diluted with DCM, washed with 1N NaOH, dried, and concentrated. The residue was subjected to flash column chromatography with 0 to 10% EtOAc in DCM to give (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (11.0 g, 91%). To a solution of (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (850 mg, 2.36 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 190 mg, 4.72 mmol). The mixture was stirred at RT for 10 min and then iodomethane (0.44 mL, 7.08 mmol) was added. The mixture was stirred at RT for 1 h, and diluted with 150 mL EtOAc. The mixture was washed with water ×2, dried, and concentrated. The residue was subjected to flash column with 0 to 3% MeOH in DCM to afford (R)-tert-butyl 3-(4-tert-butyl-N-methylbenzamido)piperidine-1-carboxylate (9) in quantitative yield. It was treated with 15 mL 4N HCl in dioxane at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-4-tert-butyl-N-methyl-N-(piperidin-3-yl)benzamide (10) HCl salt in quantitative yield.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][NH:18][C:17]=1[CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:15])[CH3:12].[OH-].[Na+]>ClCCl.O>[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([CH:3]=[O:4])[NH:18][C:17]=1[CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:15])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A stirred solution of dichloromethane (5.5 ml) and N,N-dimethylformamide (0.2 ml) was added dropwise slowly with phosphorus oxychloride (0.184 ml, 2 mmol) under an argon atmosphere while maintaining the temperature at −10° C.˜0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at −10° C., added with the solution of 2-(2-tert-butoxycarbonylamino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.36 g, 1 mmol) in dichloromethane (2 ml) while maintaining the temperature at −10° C. ˜0° C. for 1 hour. Then the mixture was stirred for another 2.5 hours at room temperature, added with cold water, adjusted to pH 11˜12 with 10% aqueous sodium hydroxide solution, extracted with ethyl acetate (50 ml×6), washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-5-formyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (309 mg, 81.9%) as a red oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][CH2:21][CH3:22])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(Br)cc(C=O)cc1OC
Temperature: 70 °C
Reaction time: 72 h
Yield: 56.9 %

Procedure:
50 g (0.43 mole) of 5-bromovanillin in 130 ml of DMF was added 150 g (1.08 mole) of potassium carbonate and 55 ml (0.606 mole) of bromopropane. The mixture was stirred for 72 hours at 70 ° C. The solution was then poured into 1 liter ice water. The aqueous solution was extracted with 3×200 ml CH2Cl2, the combined organic extracts were dried over MgSO4. The solution was filtered and the filtrate was concentrated to dryness to yield 66.80 g of 3-bromo-5-methoxy-4-propoxybenzaldehyde as a yellow oil. (95% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>CC(C)=O>[CH3:18][S:19]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1C(=O)N2C(=NC1(C)C)N(S(C)(=O)=O)c1ccccc12

Procedure:
The general procedure of Example 17 was employed to prepare the title compound by reaction of 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one, methanesulfonyl chloride and triethylamine in acetone solution. The title compound was isolated and purified by liquid chromatography giving a solid, mp 147° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:35])[C:14]([N:16]([C:18]2[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1[CH2:44][CH2:43]OCC1>>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:35])[C:14]([N:16]([CH3:17])[C:18]2[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[N:20][C:21]([N:22]3[CH2:44][CH2:43][N:16]([CH3:14])[CH2:18][CH2:23]3)=[N:22][CH:23]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1COCCO1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1nc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 143.5 %

Procedure:
To a solution of 0.5 g (0.89 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2-methanesulfonyl-4-o-tolyl-pyrimidin-5-yl)-N-methyl-isobutyramide in 10 ml dioxane 0.25 ml (2.23 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.37 g (71%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidin-5-yl]-isobutyramide as a colorless solid, m.p. 149°151°, MS (ISP): 580.1 (M+H+).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:28])=O>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([Cl:28])=[N:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(-c4ccccc4)cc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(-c4ccccc4)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(biphenyl-4-yl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].C(N(CC)CC)C.CS(Cl)(=O)=O.[I:24][C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[C:27]([I:32])[C:26]=1O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O.O>[I:24][C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[C:27]([I:32])[C:26]=1[O:11][CH2:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CC(C)=CCCC(C)CCO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCCC(C)CCOc1c(I)cc(I)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a stirred solution of citronellol (4.5 g, 28.8 mmol) and triethylamine (5.2 ml, 34.6 mmol, 1.2 eq) in dichloromethane (50 ml) cooled to 0° C. was added dropwise, a solution of methanesulfonyl chloride (2.46 ml, 28.8 mmol) in dichloromethane (50 ml). The solution was stirred for 1 hr at 0° C. under nitrogen and then water was added. The dichloromethane layer was dried over magnesium sulfate after washing with saturated aqueous sodium chloride and then concentrated in vacuo to give an oil. 1H-NMR (300 MHZ) spectrum of the oil indicated the desired methanesulfonate ester. The methanesulfonate ester was added to a stirred mixture of 2,4,6-triiodophenol (13.6 g, 28.8 mmol) and potassium carbonate (4.0 g, 28.8 mmol) in dimethylformamide (50 ml). The mixture was heated to 100° C. for 30 minutes and cooled to room temperature. The crude product was isolated by partitioning the reaction mixture between water and dichloromethane. The organic layer was concentrated under vacuum to give an oil. The oil was purified by flashing through basic alumina with hexanes to give the desired product in 15% yield as a light-sensitive oil.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:19][CH2:20][NH2:21])[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Ni].CO>[ClH:1].[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:19][CH2:20][NH2:21])=[CH:11][C:10]=1[O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: NCCc1ccc(N)c(OCc2ccccc2)c1

Procedure:
In the presence of Raney nickel, 3.2 g of 2-(3-benzyloxy-4-nitrophenyl)ethylamine, hydrochloride, is hydrogenated in 50 ml of methanol, thus producing, after recrystallizing the product from ethanol, 1.36 g of 2-(4-amino-3-benzyloxyphenyl)ethylamine, hydrochloride, mp 181°-184° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31].C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][O:27][S:39]([CH3:42])(=[O:41])=[O:40])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CO)c3Cl)cccn2c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-(glycoloylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (200 mg) and triethylamine (76 mg) in methylene chloride (2 ml) was dropwise added mesyl chloride (52 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give 3-bromo-8-[2,6-dichloro-3-[N-(mesyloxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (221 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[C:14]1([C:5]2[O:6][C:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[C:3]([CH2:2][C:20]#[N:21])[N:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1nc(-c2ccccc2)oc1-c1cccnc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(-c2ccccc2)oc1-c1cccnc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 4-(chloromethyl)-2-phenyl-5-(pyridin-3-yl)oxazole (197 mg, 728 μmol) in DMSO (4 mL) was added at RT potassium cyanide (56.9 mg, 873 μmol). Stirring was continued for 1 h and the reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (2×20 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 168 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (80 mg, 306 μmol, 42.1%).