Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([OH:29])=[O:28])[N:21]([CH3:30])[C:20]=4[CH:31]=3)[C:12](=[O:32])[CH:11]=2)=[CH:6][CH:5]=1.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([O:29][CH3:35])=[O:28])[N:21]([CH3:30])[C:20]=4[CH:31]=3)[C:12](=[O:32])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Iodomethane (0.111 ml) was added to a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (400 mg) and potassium carbonate (246 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (205 mg) as a pink solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+].[I-]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C1COCCN1
Reactant: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)ccn1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)ccn1

Procedure:
330 mg (0.90 mMol) (2-Methoxy-pyridin-4-yl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine, 0.81 ml morpholine and a trace of NaI is stirred for 2 h in 20 ml boiling ethanol. A clear solution is formed from which upon cooling to RT the title compound crystallizes out and can be filtered off; TLC (CH2Cl2/methanol 9:1) Rf=0.33; MS-ES+: (M+H)+=417.
Reaction SMILES: [I-].[F:2][CH2:3][CH2:4][N:5]([N:21]=[O:22])[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](C1[CH2+]=CC=CN1C)=[O:13])=[O:7].[CH2:23]([N:30]1[CH:38]=[CH:37][C:33](C(N)=O)=[CH:32][CH2:31]1)C1C=CC=CC=1>CO>[F:2][CH2:3][CH2:4][N:5]([N:21]=[O:22])[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]([C:37]1[CH2:33][CH:32]=[CH:31][N:30]([CH3:23])[CH:38]=1)=[O:13])=[O:7]
Reactant: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Reactant: CN1C=CC=[CH2+]C1C(=O)OCCNC(=O)N(CCF)N=O
Agent: [I-]
Solvent: CO
Product: CN1C=CCC(C(=O)OCCNC(=O)N(CCF)N=O)=C1
Yield: 55 %

Procedure:
A solution of the quaternary nitrosourea prepared in Example 126 (0.426 g, 1 mmol) and 1-benzyl-1,2-dihydroisonicotinamide (0.21 g, 1 mmol) in 25 mL of anhydrous methanol was stirred at 0° C. for 4 hours under nitrogen. The solvent was evaporated in vacuo at about 30° C. and the residue was suspended in chloroform, filtered and flash chromatographed on a short column of neutral alumina. The title compound was obtained in 55% yield after elution with chloroform and was assigned the structure ##STR154## consistent with UV analysis.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[O:7])=[N+:2]=[N-:3]
Reactant: CCNCC
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: ClCCCl
Solvent: O
Product: CCN(CC)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (8.00 g, 49.5 mmol) in anhydrous DCE (160 mL) was added diethylamine (15.4 mL, 3 equiv, 0.148 mol) in one portion. The reaction was left to stir at 0° C. for 1 h. Water (200 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with water (3×100 mL) and brine (100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (9.80 g, quant). This material was used without further purification.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:20][NH:21]C.[C-]#N.[K+]>CO>[CH2:4]([O:11][CH:12]1[CH2:17][CH2:16][C:15]([N:2]([CH3:3])[CH3:1])([C:20]#[N:21])[CH2:14][CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC(OCc2ccccc2)CC1
Reactant: CNC
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 130 ml of 7.9 molar aqueous dimethylamine solution, 16 ml of methanol, 20.0 g of 4-benzyloxycyclohexanone, 23.2 g of dimethylamine hydrochloride and 15.3 g of potassium cyanide was stirred for 65 hours at room temperature; extraction was carried out four times using 120 ml of diethyl ether each time, and the combined extracts were concentrated; 100 ml of dichloromethane were added to the residue, the phases were separated, and the organic phases were dried over sodium sulfate, filtered and concentrated. 24.5 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were obtained in the form of a yellowish oil which slowly solidified.
Reaction SMILES: [OH-].[Na+].[N:3]1([C:12]2[N:17]=[C:16]([CH3:18])[C:15]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([O:22]C)=[O:21])=[C:14]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1>CO>[N:3]1([C:12]2[N:17]=[C:16]([CH3:18])[C:15]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([OH:22])=[O:21])=[C:14]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[N:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCc3ccccc32)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCc3ccccc32)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
A solution of sodium hydroxide 5N (0.5 mL) was added to a mixture of methyl 2-(2-(indolin-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.040 g; 0.096 mmol) in methanol (1.5 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 3 and 4 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration, dried under reduced pressure over phosphorous pentoxide and purified by preparative HPLC (HPLC method 5) furnished 0.010 g (25%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5].C(N(CC)CC)C.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1>O1CCCC1>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:38](=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCNCC1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-2-(piperidin-4-ylmethyl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (100 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.14 ml) and succinic anhydride (30 mg), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from isopropyl ether to give the title compound (96 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[N:37]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)=[C:38]=[O:39]>CN(C)C(=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:40]6[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)[CH:41]=6)=[O:39])=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Nc2cccc(Oc3ccccc3)c2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 28 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.0875 M and 0.042 in N,N-dimethylacetamide, respectively, 497 μL, 0.042 mmol Example 23e and 0.126 mmol N,N-diisopropylethylamine) and 1-isocyanato-3-phenoxybenzene (0.40 M in N,N-dimethylacetamide, 208 μL, 0.084 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 150° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0067 g (28%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.90 (d, J=2.44 Hz, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.27 (m, 3H), 7.16 (m, 3H), 7.03 (m, 2H), 6.97 (s, 1H), 6.78 (m, 2H), 6.64 (m, 1H), 6.51 (m, 2H), 4.60 (m, 2H), 4.06 (s, 3H). MS (APCI+) m/z 572.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1.I[CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][OH:27])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Reactant: OCCI
Product: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1ccn(CCO)c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=368.1, 370.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCOc1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOc1ccc(OC(C)=O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.069 mL) was added to a solution mixture of the obtained 2-hydroxy-5-propoxybenzoic acid (0.12 g) in methylene chloride (3.0 mL) and pyridine (0.12 mL) under ice-cooling, followed by stirring at room temperature for 2 hours and 30 minutes. Pyridine (0.050 mL) and acetic anhydride (0.058 mL) were added to the reaction mixture, followed by stirring at room temperature for 50 minutes. The solvent was evaporated under reduced pressure, and 1 mol/L hydrochloric acid and ethyl acetate were added to the obtained residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 65-55% hexane/ethyl acetate] to obtain 0.091 g of 2-acetoxy-5-propoxybenzoic acid as a white solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)C#N)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(C)=[O:26]>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(c1cccs1)C1CCN(Cc2ccccc2)CC1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: O=C(c1cccs1)C1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 35 %

Procedure:
To a stirred mixture of 29.6 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile in 100 parts of dimethyl sulfoxide are added portionwise 4 parts of a sodium hydride dispersion 60%. Upon completion, stirring is continued overnight. The reaction mixture is poured onto water. The precipitated product is filtered off and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 10 parts (35%) of [1-(phenylmethyl)-4-piperidinyl](2-thienyl)methanone; mp. 100.5° C.
Reaction SMILES: C1(C[O:8][C:9](=[O:46])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd]>[CH2:28]([O:27][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=1)[C:9]([OH:46])=[O:8])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)O)c1
Yield: 94.3 %

Procedure:
A mixture of 14.6 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid phenylmethyl ester and 3 g of 10% palladium on carbon was shaken in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from ether-hexane to give 11.8 g (95% yield mp 79°-81°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][Cl:23].C([Li])CCC.S([O-])(O)(=O)=O.[K+]>CCCCCC.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([CH2:22][Cl:23])([OH:20])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Reactant: ClCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1COC(O)(CCl)[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (0.34 g) and bromochloromethane (0.10 ml) were added to dehydrated tetrahydrofuran (12 ml). After cooling to −78° C., 1.53 M solution (1.03 ml) of n-butyllithium in hexane was added to the obtained mixture, and they were stirred for 1 hour. 10% aqueous potassium hydrogensulfate solution was added to the reaction mixture to terminate the reaction. The temperature of the reaction mixture was elevated to room temperature. After the extraction with ethyl acetate twice, the obtained ethyl acetate layer was dried over anhydrous magnesium sulfate and then magnesium sulfate was removed. The solvent was evaporated under reduced pressure to obtain intended (4S)-N-tert-butoxycarbonyl-5-chloromethyl-5-hydroxy-4-phenylmethyloxazolidine (0.40 g) in a yield of 100%.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:30][O:31][CH2:32][CH2:33]I>CN(C=O)C.O1CCOCC1>[C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:33][CH2:32][O:31][CH3:30])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3.17 g (9.86 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-one in 190 ml of DMF/dioxane, 1:1, are treated, under an N2 atmosphere, with 6.4 g (19.7 mmol) of Cs2CO3 and 2.0 g (9.86 mmol) of 2-methoxyethyl iodide. Since HPLC indicates that unreacted 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-one is still present after 18 h at RT, a further 1.2 g of 2-methoxyethyl iodide are added in portions. As soon as HPLC indicates that the reaction is complete, the reaction mixture is poured onto 190 ml of ice-water, and the whole is extracted 3× with methylene chloride. The organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Stirring up the residue with hexane in an ultrasonication bath affords the title compound: TLC Rf (D)=0.08; FAB-MS (M+H)+ =380.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>CC(C)=O>[CH3:16][CH:15]1[CH2:17][N:3]2[N:4]=[CH:5][N:6]=[C:2]2[NH:1][C:14]1=[O:18]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1nc[nH]n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1Cn2ncnc2NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
33.63 g (0.4 mol) 3-amino-1H-1,2,4-triazole was suspended in 300 ml acetone. 44.44 g (0.44 mol) triethyl amine was added and the mixture was cooled to 0° C. 33.63 g (0.44 mol) methacryloyl chloride was added dropwise over 45 minutes, while the temperature was kept at 0° C. The reaction was allowed to continue at 0° C. for one hour. The precipitated salts were removed by filtration and an additional 10 ml triethyl amine was added to the filtrate. The mixture was refluxed for 18 hours. The precipitated compounds were removed by filtration and the solvent was evaporated under reduced pressure. 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated by preparative column chromatography on a Prochrom LC 80 system, using Kromasil C18 100 Å 10 μm silica and MeOH and an aqueous solution of 0.2% (v/v) triethyl amine and 0.5% (v/v) acetic acid in a 42/58 ratio as eluent, at a flow rate of 150 ml/min. 770 mg of 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:16]([O-])=O)[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[H][H]>[Pt].C(O)C>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([NH2:16])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CCO
Product: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.9 %

Procedure:
A mixture of 13.16 g N-butyl-N-(3'-phenylpropyl)-4-hydroxy-3-nitrobenzenesulfonamide, 2 g 1 wt % platinum on alumina, and 200 ml ethanol was stirred for 22 hours at room temperature in a bomb charged with 800 psi of hydrogen. The solution was filtered and concentrated to give 12.02 g N-butyl-N-(3'-phenylpropyl)-3-amino-4-hydroxybenzensulfonamide.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][O:4]1.N1C=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)(Cl)Cl>[O:9]=[C:7]1[CH2:6][CH2:5][O:4][CH:3]([CH2:2][O:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH2:8]1
Reactant: O=C1CCOC(CO)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CCOC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of 2-hydroxymethyl-tetrahydro-pyran-4-one (625 mg, 4.81 mmol) in a mixture of pyridine (778 μl, 9.62 mmol) and chloroform (6.0 ml) at 0° C. under nitrogen was slowly added 4-nitrobenzenesulfonyl chloride (1.60 g, 7.22 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h. Chloroform (30 ml) was added and the solution washed with 2.0 N hydrochloric acid (3×10 ml), 5% NaHCO3 (3×10 ml) and water (3×10 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated in. vacuo. The solid residue was purified by column chromatography on silica gel using a gradient of dichloromethane:hexane:ethyl acetate (1:1:0 to 8:0:2) as eluent. Pure fractions were collected and the volatiles were evaporated in vacuo affording 0.98 g (65%) of 4-nitro-benzenesulfonic acid 4-oxo-tetrahydro-pyran-2-ylmethyl ester as a solid.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[N:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CO>[C:22]([NH:26][CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[N:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1ccc(-c2ccc(OC)nn2)c(OCC2CO2)c1
Reactant: CC(C)(C)N
Solvent: CO
Product: COc1ccc(-c2ccc(OC)nn2)c(OCC(O)CNC(C)(C)C)c1
Reaction time: 24 h
Yield: 71.5 %

Procedure:
A solution of 6-[2-(2,3-epoxypropoxy)-4-methoxyphenyl]-3-methoxypyridazine (0.7 g, 0.0024 mole), t-butylamine (10.0 ml, 0.093 mole) in methanol (20 ml) was allowed to stand at room temperature for 24 hours. Evaporation of the solvent and crystallisation of the residue from ethyl acetate gave 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-methoxypyridazine (0.62 g, 70%, m.p. 114°-116°).