Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2CCOCC2)[CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[N:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: CN(C)C(=O)N1CCCCC1
Reactant: c1ccc(N2CCOCC2)c(N2CCOCC2)c1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C(=Nc1ccccc1N1CCOCC1)N1CCCCC1

Procedure:
Reaction of 1-dimethylcarbamoylpiperidine (3.7 g) in benzene (25 ml) with 4-(2-morpholinophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride for 35 hours at 80°-85° C. gave N,N-dimethyl-N'-(2-morpholinophenyl)piperidine-1-carboxamidine (m.p. 88°-90° C.) which was recrystallised from petroleum ether (b.p. 40°-60° C.)
Reaction SMILES: O=C1N2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][CH2:14][CH2:15][NH:16][S:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])=[O:11])N1OS(O)(=O)=O.FC(F)(F)[C:35](O)=[O:36].[CH2:40](Cl)Cl>>[O:36]=[C:35]1[C:6]2[C:7](=[CH:40][CH:9]=[CH:4][CH:5]=2)[C:10](=[O:11])[N:12]1[O:13][CH2:14][CH2:15][NH:16][S:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])(=[O:18])=[O:19]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a mixture of tert-butyl ({2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate 81 (0.20 g, 0.40 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h and at room temperature for 2 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 77 (Table 1) (37 mg, 23%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Br:33][C:34]1[N:39]=[C:38]([NH2:40])[CH:37]=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Br:33][C:34]1[N:39]=[C:38]([NH:40][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:19])[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cccc(Br)n1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 1.0 g, 2.65 mmol) was diluted with dichloromethane (10 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (1.46 mL, 2.92 mmol) and DMF (1 drop). After stirring for 20 minutes, 6-bromopyridin-2-amine (0.505 g, 2.92 mmol) and diisopropyl ethylamine (1.16 ml, 6.64 mmol) were added and the reaction was stirred overnight at ambient temperature, then heated to 70° C. for 4 hours. The reaction mixture was cooled, then loaded directly onto a Biotage 40 cartridge, eluting with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (500 mg, 0.940 mmol, 35.4% yield).
Reaction SMILES: [O:1]1CCOCC1.[CH3:7][O:8][CH2:9][C:10]1([C:15]#[N:16])[CH2:13][C:12](=C)[CH2:11]1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[CH3:7][O:8][CH2:9][C:10]1([C:15]#[N:16])[CH2:13][C:12](=[O:1])[CH2:11]1
Reactant: C1COCCO1
Reactant: C=C1CC(C#N)(COC)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COCC1(C#N)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of water (2 mL, 0.1 mol) and 1,4-dioxane (7 mL, 0.08 mol), 1-(methoxymethyl)-3-methylenecyclobutanecarbonitrile (0.294 g, 0.00214 mol), and 0.2 M of osmium tetraoxide in water (0.04 mL) was stirred for 5 min, during which time the mixture became brown. While the temperature was maintained at room temperature, sodium periodate (0.963 g, 0.00450 mol) was added in portions over a period of 30 min. The mixture was stirred overnight. The mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4. After removal of the solvents, the crude product was used directly in next step (298 mg, 99.92%). 1H NMR (400 MHz, CDCl3): 3.70 (2H, s), 3.68 (3H, s), 3.58 (2H, m), 3.38 (2H, m) ppm.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[NH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]1[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13]1.C(N([CH:28]([CH3:30])[CH3:29])CC)(C)C>ClCCl.CN(C=O)C>[O:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7][C:15]([C:16]12[C:28]([CH3:29])([CH3:30])[CH:20]([CH2:19][CH2:18]1)[CH2:2][C:1]2=[O:5])=[O:14]
Reactant: NCCNCC1COc2ccccc2O1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C2CCC1(C(=O)NCCNCC1COc3ccccc3O1)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To 2.0 g (10 mmole) (-)-ketopinic acid in 100 ml of dichloromethane was added 2.0 ml (23 mmole) oxalyl choride and 2 drops of DMF. The mixture was stirred for two hours at room temperature and then concentrated to dryness in vacuum. It was redissolved in 50 ml of methylenechloride and added to a cold solution of 2.1 g (10 mmole) 2-[N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin and 1.3 g (10 mmole) diisopropylethylamine in 100 ml of dichloromethane. The mixture was stirred at room temperature overnight. It was then washed with saturated aqueous sodium bicarbonate, with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on 100 g of silica gel with chloroform as eluant, and the product crystallized from 75 ml of isopropanol with the addition of 4 ml 4 N HCl/isopropyl alcohol and 225 ml of diethyl ether to produce 1.25 g of the title compound as the hydrochloride, quarter hydrate, m.p. 164°-166° C., [α]D25 =-31.3 (MeOH).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH:50]=[N:51][C:52]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=4)=[O:53])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([CH:50]=[N:51][C:52]([O:54][CH2:55][C:56]3[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=3)=[O:53])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N=CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
15 ml of trifluoroacetic acid and 460 μl of trifluoromethanesulfonic acid were added to a solution of 2.50 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(N-4-nitrobenzyloxycarbonylformimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred for 1 hour, whilst ice-cooling. The solvent was removed by distillation under reduced pressure, and the resulting residue was washed with diethyl ether, to give 2.55 g of (2S,4S)-4-mercapto-2-[4-(N-4-nitrobenzyloxycarbonylformimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate as a powder. The whole of this product was dissolved in a mixture of ethyl acetate and water, and the solution was made alkaline by adding an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated and washed with water and with an aqueous solution of sodium chloride, in that order. The solution was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 2.0 g of the title compound, as a powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCNCc1ccccn1
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1
Product: CCN(Cc1ccccn1)C(=O)CN(c1cccc(C)c1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12](N3CCOCC3)[C:11]([CH3:21])([CH3:20])[C:10]=2[CH:22]=1)(=[O:4])=[O:3].[OH2:23]>Cl>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:23])[C:11]([CH3:21])([CH3:20])[C:10]=2[CH:22]=1)(=[O:4])=[O:3]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1N1CCOCC1
Reactant: O
Agent: Cl
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O

Procedure:
A suspension of 2,3-dihydro-3,3-dimethyl-2-morpholinobenzofuran-5-yl methanesulphonate (product of Example 2) (24.9 parts) in water (50 parts) and hydrochloric acid (22.4 parts) was rapidly heated to 90°-100° C and then cooled after 2 minutes. The crude product was extracted into ether (3 × 60 parts) and the extracts washed with water (2 × 50 parts), dried with sodium sulphate and evaporated to leave a gum which crystallised to give 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methanesulphonate, m.p. 69°-72° C (16 parts)
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3=[CH:17][S:18][CH:19]=[C:13]3[NH:12][C:11]2=[S:20])=[CH:6][C:5]=1[CH:21]=[C:22]([Cl:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[C:29](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3=[CH:17][S:18][CH:19]=[C:13]3[N:12]=[C:11]2[S:20][CH3:29])=[CH:6][C:5]=1[CH:21]=[C:22]([Cl:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=S)[nH]c3cscc3c2=O)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)=Cc1cc(-n2c(SC)nc3cscc3c2=O)ccc1Cl
Temperature: 10 °C
Reaction time: 48 h

Procedure:
0.28 g of methyl iodide in 5 ml of dimethylformamide was added to a solution of 0.8 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl]-4-oxo-2-thioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine and 0.27 g of potassium carbonate in 40 ml of dimethylformamide. Stirring was carried out for 2 days, after which the mixture was cooled to 10° C., 80 ml of water were added and stirring was effected for a further 2 hours. The resulting precipitate was removed, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Yield: 86.7 %

Procedure:
To a solution of methyl 3-aminobenzoate (6.0 g) and triethylamine (4.5 g) in methylene chloride (90 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (4.8 g). The mixture was stirred for one hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water, followed by drying and concentration to dryness. The concentrate was crystallized from ethyl acetate-hexane to afford colorless prisms (8.1 g, 87%), m.p. 101-102° C. 1H-NMR(90 MHz, CDCl3) δ: 0.93(3H,t), 1.2-1.9(4H,m), 2.37(2H,t), 3.90(3H,s), 7.36(1H,t), 7.5(1H,br s), 7.70-7.95(2H,m), 8.03(1H,t).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH2:24][OH:25])[CH2:4][O:5][CH2:6][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][CH3:23].[Cl:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31]>ClC(Cl)C>[Cl:26][CH2:27][CH2:28][NH:29][C:30]([O:25][CH2:24][C@@H:3]([CH2:4][O:5][CH2:6][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][CH3:23])[O:2][CH3:1])=[O:31]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OC
Reactant: O=C=NCCCl
Solvent: CC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)NCCCl)OC
Temperature: 80 °C

Procedure:
A solution of 0.17 g of (S)-2-O-methyl-1-O-octadecylglycerine in 10 ml of dichloroethane is treated with 1 ml of 2-chloroethyl isocyanate and heated at 80° C. for 25 hours. The solution is evaporated and the residue is chromatographed on silica gel. After elution with dichloromethane-ether (9:1), there is obtained (R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-methyl-3-O-octadecylglycerine in the form of an oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([CH2:21][OH:22])[S:20][C:16]=2[CH:15]=1.C(Cl)Cl>O>[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([CH2:21][O:22][S:9]([CH3:8])(=[O:11])=[O:10])[S:20][C:16]=2[CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc2ccc(F)cc2s1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nc2ccc(F)cc2s1
Reaction time: 1 h
Yield: 94 %

Procedure:
0.08 ml of triethylamine and 0.05 ml of methanesulfonyl chloride were added to a solution of 93.1 mg of 6-fluoro-2-hydroxymethylbenzothiazole [prepared as described in step (b) above] in 1.8 mi of methylene chloride cooled in an ice-water bath. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 1 hour. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed consecutively with water and an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 125.3 mg (yield 94%) of the title compound as a solid having a melting point of 68° to 72° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37]C)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([O:32]C)[CH:25]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([OH:37])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(O)c(O)c2)cc1O
Temperature: -70 °C

Procedure:
1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane was dissolved in dry CH2Cl2 and cooled to -70° C. under inert atmosphere. BBr3 was added. The mixture was warmed to room temperature and CH3OH was added. The solvent was removed in vacuo to give 1,6-bis-[2-(3,4-dihydroxybenzyl)pyrrolidin-1-yl]hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH2:13][CH2:14][O:15][CH3:16])[N:8]=[CH:7][NH:6][C:5]2=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[C:42]([C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47])#[CH:43]>ClCCCl.C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH2:13][CH2:14][O:15][CH3:16])[N:8]=[CH:7][N:6]=[C:5]2[NH:47][C:46]1[CH:48]=[CH:49][CH:50]=[C:44]([C:42]#[CH:43])[CH:45]=1
Reactant: COCCSc1cc2nc[nH]c(=O)c2cc1Cl
Reactant: C#Cc1cccc(N)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: CC(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: C#Cc1cccc(Nc2ncnc3cc(SCCOC)c(Cl)cc23)c1
Product: Cl

Procedure:
6-Chloro-7-(2-methoxyethylsulfanyl)-quinazolin-4-one (200 mg, 0.739 mmol), triphenylphosphine (427 mg, 1.63 mmol) and 0.7 mL of carbon tetrachloride were refluxed in 4 ml of 1,2-dichloroethane for 4 hours, concentrated in vacuo to a residue, diluted with 4 mL of isopropyl alcohol and 3-ethynylaniline (129 mg, 1.104 mmol) and refluxed for 16 hours. The hot reaction mixture was filtered to isolate crude product which was column chromatographed on silica gel eluted with 5% methanol in chloroform. Fractions containing the pure product were concentrated in vacuo to afford the title product as a solid; 23 mg (8.4%); mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[F:35][CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:38][CH2:37][CH2:36][F:35])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: NCCF
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCCF
Yield: 79.3 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (250 mg, 0.50 mmol), 2-fluoroethylamine hydrochloride (100 mg, 1.00 mmol), WSC hydrochloride (288 mg, 1.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol), to obtain 216 mg of the title compound as a white solid (79%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][CH2:22][CH2:23][Cl:24])[CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][S:19]([CH2:18][C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: ClCCCCSCc1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCCCCl)Cc1cccnc1
Reaction time: 17 h
Yield: 23 %

Procedure:
A solution of 85% pure m-chloroperbenzoic acid (107 g) in methylene chloride (900 cc) is added dropwise, in the course of 1 hour 30 minutes, at a temperature of about 20° C., to a solution of 4-chlorobutyl pyridin-3-yl-methyl sulphide (103 g) in methylene chloride (900 cc). After stirring for 17 hours at the same temperature, a 10% (by weight) aqueous solution of sodium bicarbonate (3 liters) is added slowly. The organic solution is decanted and then washed with a 10% solution of sodium bicarbonate (1 liter). The aqueous phases are combined and extracted with methylene chloride (500 cc). The organic extracts are combined and washed twice with distilled water (2 liters in total), dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) at 35° C. The product obtained (87 g) is chromatographed on neutral silica gel (400 g) contained in a column of diameter 4.7 cm. Elution is carried out with methylene chloride (10 liters), three 1 liter fractions, ten 100 cc fractions and twelve 500 cc fractions being collected successively. Fractions 11 to 25 are combined and concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) at 35° C. to give 3-(4-chlorobutyl)sulphinylmethylpyridine (25.4 g) in the form of an orange oil [Rf=0.22; chromatography on a thin layer of silica gel; solvent: ethyl acetate/methanol (80/20 by volume)].
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]1=[O:13].[CH3:14][O:15][C:16]([C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1)=[O:17].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][O:15][C:16]([C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][O:13][C:3]3[N:4]=[C:5]4[CH:12]=[CH:11][CH:10]=[CH:9][N:6]4[C:7](=[O:8])[C:2]=3[CH3:1])=[CH:30][CH:31]=2)=[O:23])=[CH:20][CH:19]=1)=[O:17]
Reactant: CC1C(=O)N=C2C=CC=CN2C1=O
Reactant: COC(=O)c1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)c2ccc(COc3nc4ccccn4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methylpyrido[1,2-a]pyrimidine-2,4-dione (2.20 g, 12.5 mmol) and 4-(4-methoxycarbonylbenzoyl)benzyl bromide (7.04 g, 12.7 mmol) in DMF (40.0 ml)-DMSO (20.0 ml) was added potassium carbonate (3.92 g, 28.4 mmol) and the mixture was stirred at room temperature overnight. This reaction mixture was diluted with water and the resulting crystals were collected by filtration, dissolved in ethyl acetate, and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was re-crystallized from ethyl acetate to provide colorless needles.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Li]CCCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[CH3:1][C:2]1([C:8]2[CH:13]=[C:12]([B:26]([OH:27])[OH:25])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(Br)cc1C1(C)CCCCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(B(O)O)cc1C1(C)CCCCC1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a mixture of 2-(1-methylcyclohexyl)-4-bromoanisole (13.66 g, 0.0482 mol) in THF (121 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (33.2 mL, 1.6 M, 0.053 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was allowed to warm to RT overnight. The resulting mixture was cooled to 0° C. and 1.0 N HCl (150 mL) was slowly added. After warming to RT the mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting yellow oil was purified on silica gel (eluent: CH2Cl2:MeOH, 100 to 92:2) to afford 3-(1-methylcyclohexyl)-4-methoxyphenyl boronic acid (7.72 g, 64%) as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 120 (s, 3H), 1.40–1.85 (m, 8H), 2.00–2.10 (m, 2H), 3.75 (s, 3H), 6.90 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.66 (brs, 1H), 7.81 (s, 2H).