Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C@H:10]1[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:24][C@H:11]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:47][C:48]1[N:56]=[C:55]2[C:51]([NH:52][CH:53]=[N:54]2)=[C:50]([NH:57]C(=O)C)[N:49]=1)(=O)C>C(Cl)Cl.C(Cl)CCl>[NH2:47][C:48]1[N:56]=[C:55]2[C:51]([N:52]=[CH:53][N:54]2[C@@H:11]2[O:24][C@H:25]([CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:10]2[O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:50]([NH2:57])[N:49]=1
Reactant: O=C(O[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1

Procedure:
Dry HCl gas was bubbled into a solution of 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-β-D-arabinofuranose (17 g, 30 mmol) in CH2Cl2 (187 ml) at -10°-0° for 21/2 hr. The precipitated p-nitrobenzoic acid was removed by filtration and washed with CH2Cl2. The CH2Cl2 solution was evaporated in vacuo. The residue, dissolved in 500 ml of ethylene chloride, was added to a mixture of 2.6-diacetamidopurine (7.03 g, 30 mmol) and molecular sieve (Linde 4A, 75 g) in 500 ml of ethylene chloride. This mixture was refluxed until all the chlorosugar was consumed (TLC) (8-11 days). The mixture was then stirred with Celite and filtered. The solid was washed with CHCl3, and the combined filtrates were evaporated to dryness in vacuo. The residue was dissolved in benzene and filtered (to remove unreacted 2,6-diacetamidopurine). The filtrate was again evaporated to dryness in vacuo and the residue dissolved in 100 ml of 1 N methanolic NaOMe. After a 3-hr reflux period, the solution was chilled, neutralized with acetic acid, and refrigerated overnight. The solid that precipitated was removed by filtration, washed with MeOH, and dried in vacuo; yield 5.6 g (34%); mp 159°-161°; TLC homogenous.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]([NH:10][CH2:11][C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C1C=CN=CC=1)C.ClCCl>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]([NH:10][CH2:11][C:12]1([CH2:18][C:19]([O:21][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9]
Reactant: OCc1ccccc1
Reactant: O=C(O)CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.4 %

Procedure:
To a stirred solution of compound (49) (0.5 g, 1.67 mmol), 1,3-dicyclohexylcarbodiimide (1.0 g, 5.0 mmol) and DMAP (19 mg, 0.16 mmol) in dichloromethane (100 mL) at room temperature under nitrogen atmosphere was added benzyl alcohol (1.1 mL, 10 mmol). The reaction mixture was stirred at room temperature for 15 h (monitored by tlc and LC/MS), then filtered, and the white solid was washed with dichloromethane (2×15 mL). The combined filtrates were washed with water (2×25 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluant to provide 0.51 g (78%) of compound (50) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ1.36–1.75 (14H, m); 1.99–2.10 (2H, m); 2.35 (2H, s); 3.17 (2H, d, J=6.8 Hz); 4.05 (1H, m); 4.65 (1H, m); 5.12 (2H, s); 5.34 (1H, t, J=6.8 Hz); 7.36 (5H, m). MS (ESI): m/z=390.22 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH2:31][NH:32][CH2:33][C:34]2[S:38][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][N:22]([S:39]([C:37]3[S:38][C:34]([CH2:33][NH:32][CH2:31][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:35][CH:36]=3)(=[O:40])=[O:41])[CH2:21][CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(CNCc2ccccc2)s1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccc(CNCc5ccccc5)s4)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 5-{[(phenylmethyl)amino]methyl}-2-thiophenesulfonyl chloride (45.3 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (20 mg, 34%).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([O:31][CH3:32])=[O:30])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:20])[N:19]=2)[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1.[CH2:33]([OH:35])[CH3:34]>O.[Fe]>[CH3:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([O:31][CH3:32])=[O:30])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:20])[N:19]=2)[CH:11]=[C:12]([NH:14][C:33](=[O:35])[CH3:34])[CH:13]=1
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cc([N+](=O)[O-])cn12
Reactant: CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cc(NC(C)=O)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of iron powder (145 mg) and ammonium chloride (15 mg) in ethanol (12 ml) and water (2.2 ml) was added 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-6-nitro-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (360 mg) and the mixture was refluxed for 40 minutes. The inorgnic materials were removed by filtration and the solvent was evaporated under reduced pressure. An aqueous solution of sodium bicarbonate (5 ml) was added to the residue and the resultant solid was collected by filtration. The solid was dissolved in methylene chloride (10 ml) and acetic anhydride (94 mg) was added thereto. After stirring for 1 hour at room temperature, the organic layer was washed with an aqueous solution of sodium bicarbonate and then with water. The solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (10 g), eluting with a mixture of chloroform and methanol (100:3). The fractions containing the desired product were combined, and the solvent was removed under reduced pressure. The residue was triturated with a mixture of ethanol and diethyl ether (1:1) to give 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-6-acetamido-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (70 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>CN(C=O)C>[CH2:24]([O:17][C:3]1[CH:4]=[CH:5][C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)=[CH:7][C:2]=1[Br:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCCN1CCOC(c2ccc(O)c(Br)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCN1CCOC(c2ccc(OCc3ccccc3)c(Br)c2)C1
Temperature: 150 °C
Yield: 100 %

Procedure:
To the phenol from example 30 (117.5 mg 0.39 mmol) in dry DMF (10 ml) under an atmosphere of nitrogen, was added potassium carbonate (75 mg, 0.54 mmol) and benzyl bromide (0.07 ml, 0.54 mmol). The reaction mixture was heated to 150° C. for 48 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was then re-extracted with ethyl acetate (2×20 ml). The combined organic extracts were then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the crude product as a brown oil. This was purified by column chromatography on silica eluting with dichloromethane:methanol (9832) to give the title compound as a colourless oil (153 mg, 0.39 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.93 (t 3H), 1.56 (q, 2H), 2.05 (t, 1H), 2.25 (t, 1H), 2.37 (t, 2H), 2.82 (d, 1H), 2.92 (d, 1H), 3.85 (t, 1H), 4.02 (d, 1H), 4.52 (d, 1H), 5.15 (s, 2H), 6.87 (d, 1H), 7.20 (d, 1H), 7.30 (d, 1H), 7.37 (t, 2H), 7.45 (d, 2H), 7.58 (s, 1H). LRMS: m/z 392 (M-H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:26])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:17][CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC/C=C/c1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCC=Cc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, (E)-cinnamyl alcohol and DBU in dioxane. EI-MS m/e (%): 373 (M{81Br}+, 4), 371 (M{79Br}+, 4), 292 ([M—Br]+, 8),202 (14), 117(100), 115 (38),91 (17).
Reaction SMILES: [CH:1]([N:3]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[C@@H:4]([CH3:22])[C@@H:5]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7])=[O:2].N1C=CC=CC=1.FC(F)(F)C(O[C:41]1[C:46]([F:47])=[C:45]([F:48])[C:44]([F:49])=[C:43]([F:50])[C:42]=1[F:51])=O>ClCCl>[CH:1]([N:3]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[C@@H:4]([CH3:22])[C@@H:5]([CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[C:6]([O:8][C:41]1[C:42]([F:51])=[C:43]([F:50])[C:44]([F:49])=[C:45]([F:48])[C:46]=1[F:47])=[O:7])=[O:2]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O)N(C=O)OC1CCCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)N(C=O)OC1CCCCO1
Reaction time: 6 h
Yield: 59.5 %

Procedure:
To a solution of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoic acid (3.65 g, 0.009 mol) in dichloromethane (20 mL) at 25° C. is added via syringe pyridine (0.87 g, 0.011 mol) followed by pentafluorophenyl trifluoroacetate (3.1 g, 0.011 mol). The mixture is stirred for 6 h, diluted with dichloromethane and washed with 0.1 M aqueous HCl, 1 M aqueous sodium carbonate, saturated aqueous sodium chloride and dried over sodium sulfate. Concentration in vacuo followed by chromatography on silica gel with hexanes-EtOAc (2:1) as eluent gives 3.05 g (60%) of pentafluorophenyl (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[CH:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:16])[CH3:2].ClCCl.C(Cl)(=O)C(Cl)=O.C[N:34](C)C=O>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[CH:12]=[C:11]([C:13]([NH2:34])=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(=O)O)ccc1C
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(C(N)=O)ccc1C

Procedure:
The compound (8.03 g, 24.8 mmol) obtained in step D was added to dichloromethane (160 ml), oxalyl chloride (3.0 ml, 35 mmol) and a catalytic amount of N,N-dimethylformamide were added under ice-cooling with stirring, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, dissolved in tetrahydrofuran (100 ml), 28% aqueous ammonia (20 ml) was added under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (8.77 g) as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 44 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 44% of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) C26H26N6O4 (486.5) ##EQU25##
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)Cl>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([N:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Boc-Lys(Z)-OH (1 equivalent), Pro-OMe hydrochloride (1 equivalent) and TEA (1 equivalent) were dissolved in dry methylene chloride, and WSCD (1 equivalent) was added under cooling with ice. Thereafter, the mixture was stirred at room temperature for 20 hours, and the reaction mixture was washed successively with IN HCl, water, saturated aqueous sodium bicarbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel to obtain the end compound. Boc-Lys(Z)-Pro-OMe (1 equivalent) thus obtained was dissolved in dry methylene chloride, and an excess of trifluoroacetic acid was added. The mixture was stirred (for about 6 hours), and the solvent was distilled off under vacuum to obtain the end compound (oil).
Reaction SMILES: [NH:1]([C@@H:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][OH:5])N>CO.[Ni]>[NH2:1][C@@H:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][OH:5]
Reactant: NN[C@H](CO)CC1CCCOC1
Agent: [Ni]
Solvent: CO
Product: N[C@H](CO)CC1CCCOC1
Yield: 102.8 %

Procedure:
To the solution of (2S)-2-hydrazinyl-3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (5.79 g, 0.033 mol) in MeOH (100 mL) was added Raney Ni. The flask was degassed and equipped with a hydrogen inflated balloon. The flask was dipped into an ultrasound bath filled with water and sonicated for 4 hr at rt until the starting material was completely consumed. The mixture was then filtered through celite, and the filter cake was washed with MeOH (2×30 mL). Removal under reduced pressure gave (2S)-2-amino-3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (5.4 g, 90%).
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([O:17][S:40]([CH3:39])(=[O:42])=[O:41])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)O)[C@H]2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Yield: 91.1 %

Procedure:
p-Nitrobenzyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e4) (100 mg) was suspended in dichloromethane (6 ml) containing triethylamine (45 mg). The mixture was cooled to 0° and methanesulphonyl chloride (38.4 mg in 1.3 ml dichloromethane) was added dropwise over 5 minutes. After 25 minutes at 0° further quantities of triethylamine (15 mg) and methanesulphonyl chloride (13 mg) were added to the solution. After a further 10 minutes the solution was diluted with dichloromethane (10 ml) and was washed with cold water (20 ml), phosphate buffer (pH 3.1) (20 ml) and 5% NaHCO3 solution (20 ml). The organic layer was dried (MgSO4) and evaporated in vacuo to afford p-nitrobenzyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (e5) as a yellow foam (107 mg); νmax (CH2Cl2) 1780, 1700, 1625, 1525, 1350, 1330 and 1175 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[O:4].C([O-])(=O)C.[Na+]>C(O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]2[O:12][CH2:2][C:3](=[O:4])[C:5]=2[CH:10]=1
Reactant: O=C(CCl)c1cc(Cl)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1COc2ccc(Cl)cc21
Temperature: 0 °C
Yield: 75 %

Procedure:
(Ref: J. Org. Chem. 1955; 20; 813-818) A solution of 2-chloro-1-(5-chloro-2-hydroxy-phenyl)-ethanone (5 g; 24.4 mmol) in ethanol was heated to reflux for 10 minutes and sodium acetate (2 g; 24.4 mmol) was added to the hot mixture. Mixture continued to reflux an additional 10 minutes, and reaction was stoppered and chilled to 0° C. for 20 minutes. Mixture was quenched with water and mixture extracted with ethyl acetate (3×75 mL). Combined organics was washed with brine and dried over MgSO4. Crude material was purified by chromatography using 0-1% methanol/DCM to afford 5-chlorobenzofuran-3-one as a oily solid. (3.0 g; 75% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.O>C1COCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:7]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cc(Cl)ncn3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.34 mL (2.43 mmol) TEA are added to a mixture of 181 mg (1.22 mmol) 4,6-dichloropyrimidine and 300 mg (1.22 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) in 3 mL THF. The mixture is stirred for 5 min at 80° C. and for 2 h at rt. After that time, water is added and the mixture is extracted with dichloromethane (2×). The combined organic layers are dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; dichloromethane/methanol, gradient 98:2-95:5) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2CCOCC2)c2sc(N)nc12

Procedure:
(2-Methoxy-5-morpholin-4-yl-phenyl)-thiourea (5.0 g, 19 mmol) in chloroform (130 ml) are treated with bromine (960 □1) and the mixture refluxed for 18 hours. After removal of the volatile components in vacuo, the product is recrystallized from THF (2.8 g, 57%). MS: m/e=266 (M+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:16])=[CH:11][C:12]([O:14][CH3:15])=[O:13]>CO.O>[CH3:9][C:10]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C=C(C)C
Reactant: NCc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)CC(C)(C)NCc1ccccc1
Temperature: 55 °C
Yield: 27.6 %

Procedure:
To a solution of benzylamine (10.0 mL, 91.6 mmol) in 95% MeOH-water (180 mL) was added methyl 3-methyl-2-butenoate (12.3 mL, 100.8 mmol). The solution was heated at 55° C. and stirred for 2 weeks. The solution was then cooled to room temperature, concentrated in vacuo, and the residue purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to provide methyl 3-methyl-3-[(phenylmethyl)amino]butanoate (5.5893 g, 28%) as a pale yellow oil. LCMS: (M+H)+: 222.1.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([O:14]C2CCCCO2)[CH:11]=[CH:12][CH:13]=1.[Br:21]CCBr>O1CCCC1.Cl>[Br:21][C:9]1[C:8]([O:7][CH3:6])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:14]
Reactant: COc1cccc(OC2CCCCO2)c1
Reactant: BrCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
33 mL (52.8 mMol) n-butyllithium (1.6 M in hexane)were added dropwise to a solution 10 gm (48.1 mMol) tetrahydropyran-2-yl 3-methoxyphenyl ether in 100 mL tetrahydrofuran over 15 minutes. After stirring for 2.5 hours at room temperature, the reaction mixture was cooled to 0° C. and then 4.6 mL (53.2 mMol) 1,2-dibromoethane were added dropwise. The reaction mixture was then allowed to stir at room temperature for about 14 hours. The reaction mixture was then diluted with 50 mL 1 N hydrochloric acid and was stirred for 1 hour. The aqueous phase was extracted with three 100 mL portions of diethyl ether. The organic phases were combined and extracted well with 5 N sodium hydroxide. These basic aqueous extracts were combined and cooled in an ice/water bath. The pH of this aqueous solution was adjusted to about 1 with 5 N hydrochloric acid and then extracted with three 100 mL portions of diethyl ether. These ether extracts were combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 10% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 2.91 gm (30%) of a residue which crystallized upon standing.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])[CH3:21]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCOC(C)=O

Procedure:
A technical grade oleyl alcohol (HD-Ocenol®90/95, iodine value 94, hydroxyl value 210) was reacted with acetic anhydride (20 mol-% excess) for 4 hours at 118° C. The reaction mixture was then poured onto ice water and the organic phase was washed repeatedly with water. The crude ester obtained was then dried and purified by distillation. The ester obtained had an iodine value of 83 and a residual hydroxyl value of 0.9.